Poster Session I (PI 1-106)Displayed 8:00 am – 3:00 ... - Nature

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METHODS: 16 adult males participated in this open-label, SD,
parallel-group PET study to evaluate the magnitude and duration of
NK 1 -RO. Subjects received IV 150-mg fosaprepitant (n=8) or oral
165-mg aprepitant (n=8), and dexamethasone and ondansetron. Subjects
had 3 PET scans (baseline and 2 postdose scans at T max , 24, 48, or
120 hrs postdose). Blood was collected for plasma aprepitant assay at
selected time points over 120 hrs postdose.
RESULTS: After a 20-min IV infusion of 150 mg fosaprepitant,
NK 1 -RO at T max (~30 min) and 24 hrs postdose was 100%, at
48 hrs postdose it was ≥ 97%, and at 120 hrs postdose it was 41% to
75%. After oral 165 mg aprepitant, NK 1 -RO at T max (~4 hrs) and 24
hrs postdose was ≥ 99%, at 48 hrs postdose it was ≥ 97%, and at 120
hrs postdose it was 37% to 76%. Mean aprepitant plasma concentrations
at C 24hr , C 48hr , and C 72hr after 150 mg fosaprepitant were 761,
225, and 92.5 ng/mL, respectively; after 165 mg aprepitant, they were
1065, 380, and 142 ng/mL, respectively. At 24 and 48 hrs postdose,
the GMR [oral/IV] and 90% CI was 1.00 (0.99, 1.01) and 1.00 (0.98,
1.02), respectively. The NK 1 -RO levels at T max and 120 hrs postdose
are comparable as the GMR [oral/IV] and 90% CI were 1.00 (0.97,
1.03) at T max and 0.91 (0.50, 1.66) at 120 hrs postdose. NK 1 -RO by
aprepitant correlates with plasma concentration with clinically relevant
NK 1 -ROs of ≥97% at 24 and 48 hrs postdose.
CONCLUSION: SD 165 mg oral aprepitant and 150 mg IV fosaprepitant
result in equivalent brain NK 1 -RO.
OI-A-2
BNA REVEALS FM-THETA NETWORK IN A WORKING
MEMORY TASK PERFORMED UNDER DONEPEZIL AND
PLACEBO CONDITIONS. A. Reches, 1 K. Ziv, 1 I. Laufer, 1 A. B. Geva, 1
A. Gazzaley 2 ; 1 ElMindA LTD, Herzliya, Israel, 2 UCSF, San-Francisco,
CA A. Reches: 2. I am a paid consultant/employee for; Company/Drug;
Elminda. K. Ziv: 2. I am a paid consultant/employee for; Company/
Drug; Elminda. I. Laufer: 2. I am a paid consultant/employee for;
Company/ Drug; Elminda. A.B. Geva: 2. I am a paid consultant/
employee for; Company/Drug; Elminda. 5. I am a significant stockholder
for; Company/Drug; Elminda. A. Gazzaley: 1. This research
was sponsored by; Company/Drug; NIH K award. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Donepezil.
BACKGROUND: Donepezil (DPZ) has proven effective in treating
mild to moderate Alzheimer’s disease. However, reports on the positive
effects of DPZ on healthy individuals are scarce. The objective of
the current study was to test the effect of DPZ on healthy volunteers
while performing a working memory task.
METHODS: The electroencephalogram (EEG) was recorded in
14 healthy adult participants while they performed a selective face/
scene working memory task. Participants were asked to remember
faces (ignore scenes), remember scenes (ignore faces) or passively
view all stimuli. Each subject received both placebo and DPZ (5 mg,
orally) on two different visits in a double blinded study. To differentiate
between conditions we used a network-oriented analysis method
(Brain Network Analysis [BNA] algorithm) that seeks spatio-temporal
interrelations among multi-sited ERP activity peaks in a group of
subjects.
RESULTS: The BNA algorithm revealed a distinguishing network
(P

aBsTraCTs nature publishing group
BACKGROUND: Most methods for measuring drug effects on
the CNS rely on subjective assessments. The present research project
focused on objective measures to assess the stimulant effect of armodafinil.
The hypothesis was that the drug-related effects on alertness,
EEG and drug concentrations are correlated.
METHODS: In a double-blind, placebo-controlled, cross-over
design, this study involved six healthy adults who participated were in
three sessions. In each session, the subjects underwent 24-hour sleep
deprivation after which a single oral dose of the test drug was administered
(placebo, armodafinil 150 mg or 250 mg). The subjects underwent
12-hour sleep deprivation post-dose during which psychomotor
vigilance task, go/no-go task, EEG recording and blood sampling were
simultaneously performed. Event-related potential (ERP) analysis was
conducted in BESA ® . A simultaneous PK/PD fitting was performed
using a non-linear mixed-effects approach in NONMEM 7.
RESULTS: Armodafinil effect on alertness was correlated with
the effect compartment drug concentrations by an E max model. The
population estimates of ke0, E max (fraction of baseline) and EC50
were 0.568 (± 0.219) h -1 , 0.345 (±0.031) and 2.77 (±1.82) μg mL -1 ,
respectively. The time-varying baseline was described by a quadratic
function. Armodafinil pharmacokinetics was best described by a onecompartment
model with first-order elimination and absorption with
lag-time. Overall, the increase in alertness was accompanied by an
increase in the amplitude of the positive ERP peak at around 380 ms
(Pearson’s correlation, r=-0.74, p=1.62.10 -7 ).
CONCLUSION: Armodafinil increased the alertness of sleep
deprived adults which showed to be correlated with the effect compartment
drug concentrations. A significant correlation between alertness
and event-related changes on EEG brings the possibility of utilizing
EEG to describe the armodafinil response.
PI-1
MIRTAZAPINE SUPPRESSES THE INCREASES IN PLASMA
LEVELS OF ADRENOCORTICOTROPIC HORMONE AND NEU-
ROPEPTIDE Y UNDER CONTINUAL STRESS EXPOSURE.
K. Arao, Y. Makihara, Y. Suzuki, T. Abe, Y. Sato, M. Takeyama; Oita
University Hospital, Oita, Japan. K. Arao: None. Y. Makihara:
None. Y. Suzuki: None. T. Abe: None. Y. Sato: None. M. Takeyama:
None.
BACKGROUND: Some depressions are presumed to result
from changes in levels of stress-related hormones released from the
hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous
system (SNS), represented by adrenocorticotropic hormone
(ACTH) and neuropeptide Y (NPY), respectively. Venipuncture for
blood sampling has been proposed to be a stress factor that increases
circulating ACTH and NPY levels. We examined the effects of mirtazapine
on plasma levels of ACTH- and NPY-like immunoreactive
substances (IS) in healthy subjects under continual stress induced by
repetitive venipunctures for blood sampling.
METHODS: An open-labeled crossover study was conducted
on eight healthy volunteers. Each subject was administered a single
oral dose of mirtazapine (15 mg, Reflex Tablet, Meiji Seika Co. Ltd.,
Osaka) or placebo at an interval of one month. Venous blood samples
were collected repetitively before and after each administration.
Plasma levels of ACTH- and NPY-IS were measured using a highly
sensitive enzyme immunoassay.
RESULTS: In the placebo group, plasma ACTH-IS levels at
240 min and NPY-IS levels at 40 min increased significantly compared
with the levels before administration, presumably due to stress.
Oral administration of mirtazapine resulted in significant decreases in
plasma ACTH-IS level at 60 and 240 min and NPY-IS level at 20 and
40 min compared with placebo administration.
CONCLUSION: A single oral dose of mirtazapine modulated
plasma levels of ACTH- and NPY-IS under stress conditions. These
findings suggest that the antidepressant activity of mirtazapine may
involve the suppression of not only the HPA axis but also the SNS.
PI-2
BOTH CYP2C19 AND PON1 GENOTYPES ARE ASSOCI-
ATED WITH THE CLINICAL OUTCOME OF CLOPIDOGREL
IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION BUT
NOT ANGINA.H. Kim, 1 K. Chang, 2 Y. Koh, 3 M. Park, 4 Y. Choi, 5
C. Park, 5 S. Lee, 6 M. Oh, 6 S. Lee, 6 E. Kim, 1 J. Shon, 1 E. Chu, 2
H. Park, 2 P. Kim, 2 S. Her, 4 D. Kim, 7 J. Lee, 3 H. Kim, 8 K. Yoo, 9
D. Jeon, 10 W. Chung, 2 K. Seung, 2 J. Shin 1 ; 1 Department of Pharmacology
and Clinical Pharmacology, Inje University College of Medicine
and Busan Paik Hospital, Busan, Korea, Republic of, 2 Cardiovascular
Center and Cardiology Division, Seoul St. Mary’s Hospital and College
of Medicine, The Catholic University of Korea, Seoul, Korea, Republic
of, 3 Department of Cardiology, Catholic University Uijeongbu
St. Mary’s Hospital, Uijeongbu, Korea, Republic of, 4 Department of
Cardiology, Catholic University Daejeon St. Mary’s Hospital, Daejeon,
Korea, Republic of, 5 Department of Cardiology, Catholic University
Yeouido St. Mary’s Hospital, Seoul, Korea, Republic of, 6 Department
of Pharmacology and PharmacoGenomics Research Center, Inje University
College of Medicine, Busan, Korea, Republic of, 7 Department
of Cardiology, Catholic University St. Paul’s Hospital, Seoul, Korea,
Republic of, 8 Department of Cardiology, Catholic University Bucheon
St. Mary’s Hospital, Bucheon, Korea, Republic of, 9 Department of
Cardiology, Catholic University St. Vincent’s Hospital, Suwon, Korea,
Republic of, 10 Department of Cardiology, Catholic University Incheon
St. Mary’s Hospital, Incheon, Korea, Republic of. H. Kim: None.
K. Chang: None. Y. Koh: None. M. Park: None. Y. Choi: None.
C. Park: None. S. Lee: None. M. Oh: None. S. Lee: None. E. Kim:
None. J. Shon: None. E. Chu: None. H. Park: None. P. Kim: None.
S. Her: None. D. Kim: None. J. Lee: None. H. Kim: None. K. Yoo:
None. D. Jeon: None. W. Chung: None. K. Seung: None. J. Shin:
None.
BACKGROUND: The effect of CYP2C19 and PON1 genotypes
on the clinical outcome of clopidogrel therapy are different in patients
with PCI from stable angina and from AMI, especially in Asian populations
whose genetic profiles of CYP2C19 PM and PON1 Q192R are
different from other ethnic populations. This study was addressed to
evaluate the effects of CYP2C19 and paraoxonase-1 (PON1) genotypes
on the clinical outcome of clopidogrel in the patients with angina
and acute myocardial infarction (AMI) after undergoing percutaneous
coronary intervention (PCI).
METHODS: From the genetic association study, the functional
variants of 7 candidate genes were evaluated for the clinical outcome
of clopidogrel therapy in 2188 patients (532 AMI and 1656 angina)
undergoing PCI. The primary clinical outcome was measured for
major cardiac and cerebrovascular event (MACCE) during 1 year
follow-up.
RESULTS: Both CYP2C19 poor metabolizer (PM) and PON1
QQ192 genotype were significantly associated with higher risk of
MACCE in patients who received emergency PCI from AMI, not an
elective PCI from angina. However, the effect on platelet P2Y12 reactivity
unit was only associated with CYP2C19 PM genotype, not by
PON1 QQ192 genotype. The risk of MACCE was highest when both
genotypes of CYP2C19 PM and PON1 QQ192 were combined in AMI
subpopulation (adjusted hazard ratio [HR] (95% confidence interval
[CI]), 10.16 (2.84-36.40), p

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self-reports are often unreliable, a biomarker of alcohol use during
pregnancy is needed to accurately determine fetal exposure. Ethyl glucuronide
(EtG) is a direct metabolite of ethanol that has been detected
in the meconium, or first stool of life, of infants born to mothers who
consumed alcohol during pregnancy. The purpose of this study was
therefore to determine to what extent EtG crosses the human placenta.
METHODS: Placentae (n=4) from consenting women undergoing
elective Caesarian section at St. Michael’s Hospital in Toronto,
Ontario were taken to the on-site perfusion laboratory. After cannulation
and establishment of dual circulation, 1 μg/mL EtG was added
to the maternal reservoir and samples were taken throughout the 3 h
experiment. Measurements of placental viability were oxygen transfer,
pH, glucose consumption, hCG production, fetal reservoir volume, and
fetal arterial inflow pressure. EtG was analyzed by GC-MS after solid
phase extraction.
RESULTS: After 3 h, a fetal-to-maternal ratio of 0.29 was reached,
however EtG had not reached steady state between the 2 circulations
as net maternal-to-fetal transfer was still occurring at the end of the
experiment (Figure). Placental validation markers were within normal
ranges for all perfusions.
CONCLUSION: EtG appears to cross the human placenta and,
hence, represent both maternal and fetal load of alcohol.
EtG Concentration (ng/mL)
1400
1200
1000
800
600
400
200
0
0 20 40 60 80100 120 140 160 180 200
–200
Time (minutes)
Maternal
Fetal
PI-4
HAIR COCAETHYLENE AS A BIOMARKER OF ALCOHOL
AND COCAINE CO-EXPOSURE. A. Natekar, K. Aleksa, G. Koren;
The Hospital for Sick Children, Toronto, ON, Canada. A. Natekar:
None. K. Aleksa: None. G. Koren: None.
BACKGROUND: Cocaethlyene (CE) is a metabolite formed during
cocaine and alcohol co-consumption. CE is pharmacologically
active, prolonging cocaine-related effects, and is found in human hair.
Currently, there are no studies that have clinically validated its use in
drug testing.
METHODS: Participants were referred to the Motherisk Laboratory
for hair testing by social workers, lawyers, and other professionals.
Since September 1, 2010, 588 participants were tested.
We used liquid-liquid extraction and solid-phase microextraction
to isolate cocaine, CE, benzoylecgonine (>=5% of cocaine indicates
use), and fatty acid ethyl esters (FAEE), a biomarker of alcohol
consumption. Analysis was performed using GC-MS. Logistic
Regression, Mann-Whitney Test, and a Chi-Square Test was performed
on the data.
RESULTS: Out of 588 individuals tested for cocaine and chronic
alcohol abuse, 202 individuals were confirmed cocaine users. Of these,
99 individuals were positive for both cocaine use and FAEE, representing
42.1% of FAEE positive results. There was difficulty identifying
CE compared to BZE, as the two metabolites have similar retention
times on GC-MS. The Chi-Square Test found a P

aBsTraCTs nature publishing group
CONCLUSION: Single dose add-on of SAR to amlodipine on Day
1 or on Day 10 resulted in an additional SBP / DBP drop compared to
amlodipine alone, suggesting a synergistic effect on smooth muscle cell
constriction. This additive effect is no longer seen when parallel doses of
SAR + amlodipine were continued for 9 days since no additional decrease
in SBP / DBP was observed on Day 9 compared to amlodipine alone.
PI-6
IDENTIFYING DIGOXIN DRUG INTERACTION POTENTIAL
BY RECEIVER OPERATING CHARACTERISTIC ANALYSIS. H.
Ellens, 1 C. A. Lee, 2 J. Bentz, 3 J. Palm, 4 K. Herdi-Szab, 5 M. E. Taub, 6
D. Bednarczyk, 7 E. Perloff, 8 C. Funk, 9 P. Balimane, 10 L. Salphati, 11
A. Guo, 12 I. Hanna, 13 C. Xia, 14 L. Li, 15 G. Xiao, 16 H. Wortelboer, 17
D. Weitz, 18 A. Pak, 19 E. Reyner, 2 J. Taur, 20 X. Chu, 21 T. Yamagata, 22
S. Deng, 23 G. Rajaraman 24 ; 1 GlaxoSmithKline, Philadelphia, PA, 2 Consultant,
Carlsbad, CA, 3 Drexel University, Philadelphia, PA, 4 Astra-
Zeneca, Molndal, Sweden, 5 Solvo, Szeged, Hungary, 6 Boehringer
Ingelheim, Ridgefield, CT, 7 Novartis, Boston, MA, 8 BD Biosciences,
Boston, MA, 9 Roche, Basel, Switzerland, 10 Bristol Meyers Squibb,
Princeton, NJ, 11 Genentech, San Francisco, CA, 12 Roche, Nutley, NJ,
13 Novartis, East Hanover, NJ, 14 Millenium, Boston, MA, 15 Absorption
Systems, Exton, PA, 16 BiogenIdec, Boston, MA, 17 TNO Quality of Life,
Utrecht Area, Netherlands, 18 Sanofi-Aventis, Frankfurt, Germany, 19 Eli
Lilly, Indianapolis, IN, 20 Eisai, Boston, MA, 21 Merck, Rahway, NJ,
22 Merck Serono, Grafing, Germany, 23 Pfizer, La Jolla, CA, 24 CellzDirect,
Austin, TX. H. Ellens: None. C.A. Lee: None. J. Bentz: None. J. Palm:
None. K. Herdi-Szab: None. M.E. Taub: None. D. Bednarczyk: None.
E. Perloff: None. C. Funk: None. P. Balimane: None. L. Salphati:
None. A. Guo: None. I. Hanna: None. C. Xia: None. L. Li: None.
G. Xiao: None. H. Wortelboer: None. D. Weitz: None. A. Pak: None.
E. Reyner: None. J. Taur: None. X. Chu: None. T. Yamagata: None.
S. Deng: None. G. Rajaraman: None.
BACKGROUND: Digoxin, an orally administered cardiac glycoside,
has a narrow therapeutic window and is susceptible to transporter-mediated
drug interactions (DDI). Recent in vitro methods to
predict potential clinical digoxin DDIs of new candidate drugs have
centered on the ability to inhibit P-glycoprotein (P-gp). The objectives
of this study were to apply statistical Receiver Operating Characteristic
(ROC) analysis to define new in vitro cut-off values to anticipate
potential digoxin DDIs using Pgp expressing cell lines and vesicles.
METHODS: Twenty-four commercial laboratories collaborated to
generate IC 50 data in three cell systems, plus vesicles, using four equations
and multiple commercial nonlinear regression programs. P-gp
inhibition data were fitted to several logistic and nonlinear regression
equations, and statistics were applied to identify robust data for variability
analysis. ROC analysis was conducted utilizing all in vitro IC 50
values generated by all companies and for individual laboratories.
RESULTS: Principal component analysis indicated that the cells/vesicles
utilized were the primary source of variability whereas the different
equations used to calculate the cell line IC 50 values were a secondary
source. The in vitro cut-off values of inhibitor maximum concentration
at steady state (I) divided by P-gp inhibitory potency (IC 50 ) of > 0.1 or
the nominal gut concentration (I 2 ) divided by IC 50 of > 10 were less predictive
of clinical digoxin DDI when all companies data were utilized
(ROC area under the curve [AUC’] < 0.7) than individual laboratory
ROC analyses, which define unique in vitro cut-off values, AUC’ > 0.8.
CONCLUSION: We propose that digoxin DDI potential is better
predicted using individual laboratory defined in vitro I/IC 50 and I 2 /IC 50
cut off values based on ROC analysis and advocate this methodology
to anticipate DDIs with digoxin.
PI-7
NO EFFECT OF PAR-1 RECEPTOR ANTAGONIST VORAPAXAR
ON QT/QTC INTERVAL IN HEALTHY VOLUNTEERS.T. Kosoglou, 1
T. L. Hunt, 2 F. Xuan, 1 B. Kumar, 1 P. Statkevich, 1 S. Young, 1 R. Hoffman, 1
A. G. Meehan, 1 D. L. Cutler 1 ; 1 Merck Sharp & Dohme Corp., Whitehouse
Station, NJ, 2 PPD Development LP, Austin, TX. T. Kosoglou: 1. This
research was sponsored by; Company/Drug; Merck. 2. I am a paid
consultant/employee for; Company/Drug; Merck. 5. I am a significant
stockholder for; Company/Drug; Merck. T.L. Hunt: 1. This research
was sponsored by; Company/Drug; Merck. F. Xuan: 1. This research
was sponsored by; Company/Drug; Merck. 2. I am a paid consultant/
employee for; Company/Drug; Merck. 5. I am a significant stockholder
for; Company/Drug; Merck. B. Kumar: 1. This research was sponsored
by; Company/Drug; Merck. 2. I am a paid consultant/employee
for; Company/Drug; Merck. 5. I am a significant stockholder for;
Company/Drug; Merck. P. Statkevich: 1. This research was sponsored
by; Company/Drug; Merck. 2. I am a paid consultant/employee for;
Company/ Drug; Merck. 5. I am a significant stockholder for; Company/
Drug; Merck. S. Young: 1. This research was sponsored by; Company/
Drug; Merck. 2. I am a paid consultant/employee for; Company/ Drug;
Merck. 5. I am a significant stockholder for; Company/Drug; Merck.
R. Hoffman: 1. This research was sponsored by; Company/Drug;
Merck. 2. I am a paid consultant/employee for; Company/Drug; Merck.
5. I am a significant stockholder for; Company/Drug; Merck. A.G. Meehan:
1. This research was sponsored by; Company/Drug; Merck. 2.
I am a paid consultant/employee for; Company/Drug; Merck. 5. I am a
significant stockholder for; Company/Drug; Merck. D.L. Cutler: 1. This
research was sponsored by; Company/Drug; Merck. 2. I am a paid consultant/employee
for; Company/Drug; Merck. 5. I am a significant stockholder
for; Company/Drug; Merck.
BACKGROUND: We evaluated the QT/QTc prolongation and
proarrhythmic potential of the PAR-1 receptor antagonist vorapaxar
(VOR) as per ICH E14 Guidance.
METHODS: This was a randomized, double-blind (for VOR &
placebo [PBO]), PBO- and positive-controlled (moxifloxacin [MOX]
400 mg) parallel group study assessing the effect of a single VOR
120 mg dose on QT/QTc interval in 120 men and women ages 18-50
yrs (n=40/group). This VOR dose achieves ~3 x the exposure (based
on C max and AUC 0-24 ) of the 40-mg loading dose and ~9 x and 5 x,
respectively, the SS exposure of the 2.5-mg QD maintenance dose.
12-lead ECGs were obtained in triplicate at 9 timepoints over 24 hrs
using Mortara H12+ Holters. If the largest upper bound of the 95%
one-sided CI for the mean difference in QTcF (primary endpoint)
between VOR and PBO was 10 msec at 1,
1.5 and 2 hrs postdose relative to PBO validating the study sensitivity.
VOR 120 mg had no significant effect on QTcF over the 23-hr postdose
evaluation period (figure); at all timepoints the upper 95% CI for
the mean difference between PBO and VOR was ≤3.8 msec and the
mean difference was ≤1.0 msec. Results of the QTcB, QTcI and uncorrected
QT analyses were concordant with the QTcF analysis.
CONCLUSION: VOR was well tolerated and had no effect on QT/
QTc interval in healthy subjects.
s10 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt
Mean (upper bound of 95% Cl)
difference between treatment vs. placebo
20
15
10
5
0
–5
0 1 2 4 6 12
Hour
MOX vs. PBO
VOR vs. PBO
23

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PI-8
PHARMACOKINETICS AND PHARMACODYNAMICS OF
MDCO-216 (APOA-I MILANO/POPC COMPLEX), A REVERSE
CHOLESTEROL TRANSPORT (RCT) INDUCER IN CYNOMOL-
GUS MONKEYS AFTER SINGLE DOSE AND 6 WEEKS OF
TREATMENT. S. E. Bellibas, B. Zerler, H. Kempen, D. Goundis,
P. Wijngaard; The Medicines Company, Parsippany, NJ. S.E. Bellibas:
1. This research was sponsored by; Company/Drug; The Medicines
Company. 2. I am a paid consultant/employee for; Company/Drug; The
Medicines Company. B. Zerler: 2. I am a paid consultant/employee for;
Company/Drug; The Medicines Company. H. Kempen: 2. I am a paid
consultant/employee for; Company/Drug; The Medicines Company.
D. Goundis: 2. I am a paid consultant/employee for; Company/Drug;
The Medicines Company. P. Wijngaard: 2. I am a paid consultant/
employee for; Company/Drug; The Medicines Company.
BACKGROUND: MDCO-216 is a complex of recombinant
dimeric apolipoprotein A-I Milano (ApoA-IM, a genetic variant of natural
ApoA-I) and POPC, a naturally occurring phospholipid. MDCO-
216 mimics pre-beta HDL in both structure and function, and in earlier
studies was shown to reduce atherosclerotic plaque size and volume
in animals and patients with ACS. The objective of this study was to
investigate the PK and PD of MDCO-216 in cynomolgus monkeys.
METHODS: Animals were randomly divided into 4 groups (3 M
and 3 F per group) and treated with vehicle or MDCO-216 at 30, 100
and 300 mg/kg dose as 60 min IV infusion every 2 days over a period
of 41 days. PK samples were taken at the end of infusion and 1, 2, 4,
8, 24 and 48 hour post-infusion. Serum lipids and apoproteins were
determined as PD parameters at baseline and on days 15 and 41 with
samples taken just prior to the next dosing.
RESULTS: MDCO-216 mean serum concentrations for M and F
monkeys were similar and increased in a dose proportional manner.
C max levels obtained at the end of infusion were 691±50 and 709±95,
2330±191 and 2020±99, 6470±975 and 6180±502 μg/mL (mean±SD)
for M and F monkeys in 30, 100 and 300 mg/kg dose groups, respectively.
PK levels appeared to decline in a bi-phasic manner with t 1/2 values
ranging from 28.4 to 42 hours. Total CL was independent of gender
and appeared to increase with escalating doses ranging from 0.0131
to 0.0207 mL/min/kg in low dose and 0.0318 to 0.0641 mL/min/kg in
high dose groups. Mean volume of distribution (Vz) values per dose
group ranged from 0.0599 to 0.192 L/kg.
CONCLUSION: MDCO-216 induced RCT with pronounced
increases in the serum levels of free cholesterol (>10-fold with the
highest dose) and phospholipids (up to 5-fold). Similar to what
was observed in individuals with the ApoA-IM mutation, levels of
ApoA-I and ApoA-II decreased by 50 and 80%, respectively. These
findings support the potential use of ApoA-IM for atherosclerotic
plaque regression as previously shown in a small study with ACS
patients.
PI-9
DRUG INTERACTION STUDY OF IPRAGLIFLOZIN AND MIGI-
TOL IN HEALTHY JAPANESE SUBJECTS. I. Nakajo, 1 Y. Taniuchi, 1
S. Yoshida, 1 T. Kadokura, 1 S. Kageyama 2 ; 1 Astellas Pharma Inc, Tokyo,
Japan, 2 Jikei University School of Medicine, Tokyo, Japan.
I. Nakajo: 1. This research was sponsored by; Company/Drug;
Astellas Pharma Inc. 2. I am a paid consultant/employee for; Company/
Drug; Astellas Pharma Inc. Y. Taniuchi: 1. This research was sponsored
by; Company/Drug; Astellas Pharma Inc. 2. I am a paid consultant/
employee for; Company/Drug; Astellas Pharma Inc. S. Yoshida:
1. This research was sponsored by; Company/Drug; Astellas Pharma
Inc. 2. I am a paid consultant/employee for; Company/Drug; Astellas
Pharma Inc. T. Kadokura: 1. This research was sponsored by;
Company/Drug; Astellas Pharma Inc. 2. I am a paid consultant/
employee for; Company/Drug; Astellas Pharma Inc. S. Kageyama:
1. This research was sponsored by; Company/Drug; Astellas Pharma
Inc. 2. I am a paid consultant/employee for; Company/Drug; Astellas
Pharma Inc.
aBsTraCTs
BACKGROUND: Ipragliflozin (ASP 1941) is a novel selective
sodium glucose co-transporter (SGLT) 2 inhibitor in development for
the treatment of type 2 diabetes mellitus (T2DM). This novel drug is
likely to be used concomitantly with other glucose-lowering drugs
like miglitol. Miglitol can be absorbed via SGLT1; ipragliflozin has a
very weak inhibitory effect on SGLT1. The aim of this drug interaction
study was to evaluate the pharmacokinetics (PK) and safety of both
drugs after dosing alone and in co-administration.
METHODS: This was a 6 sequence single-dose, 3-way crossover
study in 30 healthy Japanese male subjects. Each subject received 100
mg ipragliflozin alone, 75 mg miglitol alone or both drugs in combination
(under fasting conditions) on the administration day of each
period with at least a 6 day wash-out between each period. Primary PK
variables were C max and AUC inf . Secondary variables were t ½ , AUC last ,
CL/F and t max . Safety parameters were also assessed.
RESULTS: The geometric mean ratios (GMRs) [90% CIs] for C max
and AUC inf of ipragliflozin after co-administration with miglitol versus
ipragliflozin alone were 1.034 [0.944-1.132] and 1.015 [0.988-1.043],
respectively. The GMRs [90% CIs] for C max and AUC inf of miglitol
after co-administration with ipragliflozin versus miglitol alone were
0.761 [0.672-0.861] and 0.796 [0.719-0.881], respectively. No clinically
significant concerns were identified for ipragliflozin administered
alone or in combination with miglitol in healthy male subjects.
CONCLUSION: The PK of ipragliflozin was similar whether dosing
alone or in co-administration with miglitol, indicating no drugdrug
interactions. The C max and AUC inf of miglitol were lower after
co-administration with ipragliflozin, suggesting a decrease in absorption
and exposure to miglitol when both drugs are co-administrated,
but the effect was not considered clinically relevant.
PI-10
LACK OF PHARMACOKINETIC AND PHARMACODYNAMIC
INTERACTION BETWEEN IPRAGLIFLOZIN, A SELECTIVE
SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITOR,
AND GLIMEPIRIDE IN HEALTHY SUBJECTS. S. A. Veltkamp,
J. van Dijk, W. J. Krauwinkel, R. A. Smulders; Astellas Pharma Europe
BV, Leiderdorp, Netherlands. S.A. Veltkamp: 1. This research was
sponsored by; Company/Drug; Astellas Pharma Europe BV. 2. I am
a paid consultant/employee for; Company/Drug; Astellas Pharma
Europe BV. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Ipragliflozin. J. van Dijk: 1. This research
was sponsored by; Company/Drug; Astellas Pharma Europe BV.
2. I am a paid consultant/employee for; Company/Drug; Astellas
Pharma Europe BV. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is still
investigational; Company/Drug; Ipragliflozin. W.J. Krauwinkel:
1. This research was sponsored by; Company/Drug; Astellas Pharma
Europe BV. 2. I am a paid consultant/employee for; Company/Drug;
Astellas Pharma Europe BV. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Ipragliflozin. R.A. Smulders:
1. This research was sponsored by; Company/Drug; Astellas Pharma
Europe BV. 2. I am a paid consultant/employee for; Company/Drug;
Astellas Pharma Europe BV. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; Ipragliflozin.
BACKGROUND: Ipragliflozin (ASP 1941) is a novel SGLT2
inhibitor in development for the treatment of type 2 diabetes mellitus
(T2DM). It inhibits SGLT2-mediated glucose reuptake in the kidneys,
thereby increasing urinary glucose excretion (UGE), leading to a reduction
in plasma glucose levels in T2DM patients. The main objective
was to assess the pharmacokinetic (PK) and pharmacodynamic (PD)
interactions between ipragliflozin and glimepiride in healthy subjects.
METHODS: This was an open-label, randomized, crossover twoarm
study. Arm A (n = 26) assessed the effects of multiple oral doses of
ipragliflozin (150 mg/day for 7 days) on the PK (AUC inf and C max ) of
a single oral dose of glimepiride (2 mg). Arm B (n = 26) evaluated the
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s11

aBsTraCTs nature publishing group
effects of multiple oral doses of glimepiride (1 mg/day for 5 days) on
the PK and PD of a single dose of ipragliflozin (150 mg). The plasma
PK parameters of ipragliflozin, glimepiride, and its active metabolite
5-hydroxy-glimepiride were determined throughout the study.
RESULTS: The PK parameters of glimepiride obtained in the presence
and absence of ipragliflozin were similar. Geometric mean ratios
(GMRs) [90% CI] for AUC inf (ipragliflozin + glimepiride/glimepiride)
were 1.051 [1.013-1.090] for glimepiride and 0.998 [0.966-1.031]
for 5-hydroxy-glimepiride. GMRs for C max (ipragliflozin + glimepiride/glimepiride)
were 1.100 [1.019-1.188] for glimepiride and 1.008
[0.941-1.079] for 5-hydroxy-glimepiride. The PK parameters of
ipragliflozin were comparable between ipragliflozin + glimepiride
versus ipragliflozin alone: GMRs [90% CI] of AUC inf and C max were
0.991 [0.966-1.016] and 0.973 [0.892-1.062], respectively. No difference
was observed in the PD of ipragliflozin after ipragliflozin +
glimepiride versus ipragliflozin alone: GMR [90% CI] of UGE was
0.919 [0.876-0.963].
CONCLUSION: Concomitant administration of ipragliflozin and
glimepiride to healthy subjects did not result in a PK or PD interaction
between these two drugs.
PI-11
ETHNIC SENSITIVITY ASSESSMENT DURING DRUG
DEVELOPMENT: PAST, PRESENT AND FUTURE IN A LARGE
PHARMACEUTICAL COMPANY.C. S. Weber, 1 Y. Fukushima, 1
A. Guenther, 1 Q. Jiang, 2 S. Kim, 3 R. Li, 2 Y. Lim, 3 P. Lu, 4 R. Peck, 5
C. Rayner, 6 S. Zhai, 2 J. Zhi 4 ; 1 Fa. Hoffmann-La Roche Ltd, Basel,
Switzerland, 2 Roche R&D Center, Shanghai, China, 3 Roche Korea
Company Ltd, Seoul, Korea, Republic of, 4 Hoffmann-La Roche Inc,
Nutley, NJ, 5 Roche Products Ltd, Welwyn Garden City, United Kingdom,
6 Roche Products Pty. Ltd, Dee Why, Australia. C.S. Weber: 2.
I am a paid consultant/employee for; Company/Drug; F. Hoffmann-La
Roche Ltd, Switzerland. Y. Fukushima: 2. I am a paid consultant/
employee for; Company/Drug; F. Hoffmann-La Roche Ltd, Switzerland.
A. Guenther: 2. I am a paid consultant/employee for; Company/
Drug; F. Hoffmann-La Roche Ltd, Switzerland. Q. Jiang: 2. I am a
paid consultant/employee for; Company/Drug; Roche R&D Center
Shanghai. S. Kim: 2. I am a paid consultant/employee for; Company/
Drug; Roche Korea Company Ltd, Seoul. R. Li: 2. I am a paid consultant/employee
for; Company/Drug; Hoffmann-La Roche Inc, Nutley.
Y. Lim: 2. I am a paid consultant/employee for; Company/Drug;
Roche Korea Company Ltd, Seoul. P. Lu: 2. I am a paid consultant/
employee for; Company/Drug; Hoffmann-La Roche Inc, Nutley. R.
Peck: 2. I am a paid consultant/employee for; Company/Drug; Roche
Products Ltd, Welwyn Garden City. C. Rayner: 2. I am a paid consultant/employee
for; Company/Drug; Roche Products Pty. Ltd, Dee
Why. S. Zhai: 2. I am a paid consultant/employee for; Company/
Drug; Roche R&D Center, Shanghai. J. Zhi: 2. I am a paid consultant/
employee for; Company/Drug; F. Hoffmann-La Roche Inc, Nutley.
BACKGROUND: The question on ethnic differences in drug
response has received more attention in recent years, likely because
more clinical trials are performed and included for registration in
emerging markets. We investigated how this has been addressed during
drug development in Roche/Genentech in the past. Having identified
changes over time and lessons learned, the objective was to propose
improved future strategies.
METHODS: US labels of Roche/Genentech marketed drugs
since 1995 and corresponding labels in selected Asian countries were
reviewed for information on ethnic sensitivity. Clinical development
plans of all Roche projects in Phases 1-3 were analyzed for activities
assessing ethnic sensitivity. The more recent activities were evaluated
for their value and impact on later development phases.
RESULTS: >50% of Roche/Genentech drugs registered in the US
don’t contain any label statement in relation to findings on ethnic/racial
differences or similarities. This is true even in cases where a large data
base in Asian subjects exists. For those drugs registered more recently,
ethnicity label statements are found more frequently but are mostly limited
to differences/similarities in PK. Of the drugs in late-phase develop-
ment ≥50% generated some early PK data in Asians and Caucasians that
enabled global studies including US/EU and Asian countries. Exploratory
PK data and, in few cases PD, in Asians and Caucasians are available
for 90% of drugs currently in Phase 2. For most drug candidates in Phase
1 no concrete plans exist for studying ethnic sensitivity until proof of concept
is established. Case studies are presented to exemplify the limitations/risks
of past strategies and their impact on drug development.
CONCLUSION: Today, more and earlier ethnic sensitivity assessments
are being performed. The assessment could be improved in the
future taking into account innovative methods, the growing science in
this field and the clinical trial opportunities in Asia.
PI-12
APPLICATIONS OF EXPLORATORY CLINICAL TRIALS
IN DRUG DEVELOPMENT- REVIEW OF EXPLORATORY
TRIAL USER GROUP MEETING, WASHINGTON, JUNE 2011. I.
Shaw, 1 L. Stevens, 1 P. Mudd, 2 M. Young, 2 P. Y. Muller, 3 D. Boulton, 4
D. Spracklin, 5 C. Lambert, 6 E. Helmer, 7 M. Rizk 8 ; 1 Quotient Clinical
Ltd, Ruddington, United Kingdom, 2 Glaxo SmithKline, Research
Triangle Park, NC, 3 Novartis Institutes for BioMedical Research,
Cambridge, MA, 4 Bristol-Myers Squibb Co, Princeton, NJ, 5 Pfizer,
Groton, CT, 6 Astra Zeneca R&D, Alderley Park, United Kingdom,
7 Takeda Global Research & Development Centre (Europe), London,
United Kingdom, 8 Merck Research Laboratories, West Point, PA.
I. Shaw: None. L. Stevens: None. P. Mudd: None. M. Young:
None. P.Y. Muller: None. D. Boulton: None. D. Spracklin: None.
C. Lambert: None. E. Helmer: None. M. Rizk: None.
BACKGROUND: Requirements for exploratory trials are defined
by ICH M3 R2 and clinical data derived from such studies is recognized
by regulatory authorities worldwide. Examples in current drug
development were reviewed at a meeting in June 2011.
METHODS: 16 case studies highlighted by the following examples
were discussed at the meeting. IV microtracer use was described by a
study to generate absolute bioavailability data. The study with a DPP-4
inhibitor resulted in regulatory approval and the abbreviated approach
to IV formulation development brought the product to the market
quicker than traditional approaches would have enabled. Exploratory
FIH (eFIH) studies were exemplified by a study with a drug targeting
an anti-inflammatory receptor. The study established human PK of the
drug prior to phase IIa to justify progression of development. Microdose
utility was demonstrated through a study screening a lead candidate for
DDI liability with and without the presence of a potent CYP3A4 inhibitor.
Increases in AUC at both micro and therapeutic dose were confirmed
supporting progression/termination decisions for back-ups and
informing concomitant medication advice for subsequent studies.
RESULTS: IV tracer applications deliver cost and time savings
over conventional methods for generating IV data. ‘Piggybacking’
tracer doses onto other studies in the development portfolio limits
the impact on program budgets. eFIH studies at pharmacologic dose
have significant utility, particularly given the ability to add other study
objectives such as food effect, and IV tracer to the design. Microdosing
applications are viewed as a ‘fit for purpose’ rather than as a routine
development strategy.
CONCLUSION: Exploratory trials are challenging conventional
drug development paradigms by generating data earlier to inform key
development decisions with the potential to bring new medicines to
market quicker.
PI-13
LACK OF EFFECT OF IPRAGLIFLOZIN, A SELECTIVE
SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBI-
TOR, ON CARDIAC REPOLARIZATION IN HEALTHY MALE
AND FEMALE SUBJECTS. W. Zhang, 1 R. Smulders, 2 A. Abeyratne, 1
A. Dietz, 3 J. Keirns 1 ; 1 Astellas Pharma Global Development, Inc, Deerfield,
IL, 2 Astellas Pharma Global Development, Leiderdorp, Netherlands,
3 Spaulding Clinical Research, West Bend, WI. W. Zhang: 1. This
research was sponsored by; Company/Drug; Astellas Pharma. 2. I am
s12 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
a paid consultant/employee for; Company/Drug; Astellas Pharma. 6.
I will be discussing the following product, which is not labeled for the
use under discussion, or the product is still investigational; Company/
Drug; Ipragliflozin. R. Smulders: 1. This research was sponsored by;
Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee
for; Company/Drug; Astellas Pharma. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Ipragliflozin. A.
Abeyratne: 1. This research was sponsored by; Company/Drug; Astellas
Pharma. 2. I am a paid consultant/employee for; Company/Drug;
Astellas Pharma. A. Dietz: 1. This research was sponsored by; Company/Drug;
Astellas Pharma. 2. I am a paid consultant/employee for;
Company/Drug; Astellas Pharma. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Ipragliflozin. J. Keirns: 1.
This research was sponsored by; Company/ Drug; Astellas Pharma. 2. I
am a paid consultant/employee for; Company/Drug; Astellas Pharma.
BACKGROUND: Ipragliflozin (ASP1941), a novel, potent selective
SGLT2 inhibitor, is under development by Astellas Pharma for the
treatment of type 2 diabetes mellitus. This study assessed the effects of
repeated, oral single-dosing of ipragliflozin (100 mg and 600 mg) on cardiac
repolarization as measured by QTcF interval in healthy subjects.
METHODS: This was a randomized, double-blind, placebo and
active controlled, four-way crossover study. Eighty-eight subjects were
randomized into one of four sequences, with 22 subjects (10 male and 12
female) in each sequence. Each sequence included: Treatment A, placebo
for 7 days; Treatment B, ipragliflozin 100 mg/day for 7 days (therapeutic
dose); Treatment C, ipragliflozin 600 mg/day for 7 days (supratherapeutic
dose); and Treatment D, moxifloxacin 400 mg on day 7 only. The
washout period was at least 7 days. An analysis of covariance (ANCOVA)
was used to assess the effect of ipragliflozin on QTcF interval with
sequence, period, treatment, and treatment by time as fixed effects; subject
(sequence) as a random effect; and baseline QTcF as a covariate.
RESULTS: The upper bound of the one-sided 95% confidence
interval (CI) for the mean QTcF treatment difference from placebo,
between ipragliflozin 600 mg and placebo at each time point, was less
than 10 msec in all subjects and also by sex. The largest upper bounds
of the 95% CIs of mean treatment differences from placebo were 4.44
msec and 2.88 msec for ipragliflozin 600 mg and 100 mg in all subjects,
respectively. No subjects showed QTcF intervals > 480 msec, nor
time-matched change from baseline > 60 msec. No significant ipragliflozin-related
electrocardiogram changes were noted. Moxifloxacin
demonstrated assay sensitivity for QTcF prolongation with the lower
bound of the one-sided 95% CI > 5 msec.
CONCLUSION: Ipragliflozin did not show clinically meaningful
or statistically significant effects on cardiac repolarization in healthy
subjects at doses up to 600 mg/day.
PI-14
EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOK-
INETICS OF IPRAGLIFLOZIN, A NOVEL SODIUM GLUCOSE
CO-TRANSPORTER 2 (SGLT2) INHIBITOR. W. Zhang, 1 W. Krauwinkel,
2 J. Keirns, 1 R. Townsend, 1 K. C. Lasseter, 3 L. Plumb, 1 R.
Smulders 2 ; 1 Astellas Pharma Global Development, Inc, Deerfield,
IL, 2 Astellas Pharma Europe BV, Leiderdorp, Netherlands, 3 Clinical
Pharmacology of Miami, Inc., Miami, FL. W. Zhang: 1. This
research was sponsored by; Company/Drug; Astellas Pharma.
2. I am a paid consultant/employee for; Company/Drug; Astellas
Pharma. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Ipragliflozin. W. Krauwinkel: 1. This
research was sponsored by; Company/ Drug; Astellas Pharma.
2. I am a paid consultant/employee for; Company/Drug; Astellas
Pharma. J. Keirns: 1. This research was sponsored by; Company/
Drug; Astellas Pharma. 2. I am a paid consultant/employee for;
Company/Drug; Astellas Pharma. R. Townsend: 1. This research
was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid
aBsTraCTs
consultant/employee for; Company/Drug; Astellas Pharma. K.C.
Lasseter: 1. This research was sponsored by; Company/Drug;
Astellas Pharma. 2. I am a paid consultant/employee for; Company/
Drug; Astellas Pharma. L. Plumb: 1. This research was sponsored
by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/
employee for; Company/Drug; Astellas Pharma. R. Smulders:
1. This research was sponsored by; Company/ Drug; Astellas
Pharma. 2. I am a paid consultant/employee for; Company/Drug;
Astellas Pharma. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; Ipragliflozin.
BACKGROUND: Ipragliflozin (ASP1941), a novel potent selective
SGLT2 inhibitor, is undergoing development by Astellas Pharma for
the treatment of type 2 diabetes mellitus. It is mainly metabolized by
the liver primarily via glucuronidation. This study evaluated the effect
of moderate hepatic impairment (HI) on the pharmacokinetics (PK) of
ipragliflozin and its metabolites (M1, M2, M3, M4 and M6).
METHODS: This was an open-label, single dose study. Sixteen
subjects were enrolled (n = 8 healthy subjects and n = 8 with moderate
HI [Child-Pugh score 7-9]; groups were gender, age and body
weight matched) and received a single oral dose of ipragliflozin 100
mg. Serial blood samples were collected for up to 144 h to determine
plasma concentrations of ipragliflozin and its metabolites. Adverse
events (AEs) were monitored during the study.
RESULTS: All subjects completed the study. Mean C max and
AUC inf values of ipragliflozin were 27% and 25% higher, respectively,
in those with moderate HI versus healthy subjects (Table). No changes
in half-life and protein binding of ipragliflozin were observed in moderate
HI subjects. Mean C max and AUC inf values of M2, the major
metabolite, were similar in both populations. AEs were mild in severity
and their incidence similar in both populations.
CONCLUSION: Moderate HI had no clinically meaningful effects
on the single-dose PK of ipragliflozin and its major metabolite M2.
A single oral dose of ipragliflozin 100 mg was well tolerated both in
healthy subjects and those with moderate HI.
Ipragliflozi
n
AUC inf = area under the plasma concentration-time curve from time
of dosing to infinity; C max = maximum plasma concentration; CI =
confidence interval.
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s13
Analyte
M1
M2
M3
M4
M6
Table: Summary of statistical comparisons for ipragliflozin and its metabolites.
Parameters
(unit)
AUCinf
(ng.h/mL)
Cmax (ng/mL)
AUCinf
(ng.h/mL)
Cmax (ng/mL)
AUCinf (ng.h/mL)
Cmax (ng/mL)
AUCinf (ng.h/mL)
Cmax (ng/mL)
AUCinf (ng.h/mL)
Cmax (ng/mL)
AUCinf (ng.h/mL)
Cmax (ng/mL)
Least squares geometric
means
Healthy
subjects
8950.95
1334.69
616.11
77.95
6186.58
904.48
1453.66
149.01
1361.70
180.36
781.90
53.91
Moderate HI
subjects
11,178.27
1691.91
455.73
45.36
6177.15
858.63
1812.78
165.60
2584.40
312.95
1251.11
75.38
Ratio
124.8
8
126.7
6
73.97
58.19
99.85
94.93
124.7
0
111.1
3
189.7
9
90% CI for
ratio
93.84–166.19
92.79–173.17
35.23–155.30
25.50–132.81
76.82–129.78
67.53–133.44
92.80–167.58
77.83–158.67
122.72–293.53
173.5
114.77–262.33
2
160.0
1
139.8
4
101.14–253.14
87.97–222.28

aBsTraCTs nature publishing group
PI-15
FOLIC ACID AND COLORECTAL ADENOMA RECURRENCE:
A SYSTEMATIC REVIEW OF RANDOMIZED CONTROL TRI-
ALS. D. A. Kennedy, S. J. Stern, I. Matok, M. Moretti, M. Sarkar,
T. Adams-Webber, G. Koren; The Hospital for Sick Children, Toronto,
ON, Canada. D.A. Kennedy: None. S.J. Stern: None. I. Matok:
None. M. Moretti: None. M. Sarkar: None. T. Adams-Webber:
None. G. Koren: None.
BACKGROUND: The theory of ‘‘dual effect of folate’’ in cancer
postulates that in healthy persons folate supplementation decreases
the rates of cancer, while heightened folate exposure may increase the
rate of malignant transformation of precancerous cells. Our aim was to
examine the risk of colorectal adenoma recurrence under a high intake
of folic acid in the context of folic acid supplementation.
METHODS: MEDLINE, Embase, and SCOPUS were searched
from inception to April, 2011: using the following ‘‘folic acid,’’ ‘‘folate,”
‘‘colorectal adenomas,’’ ‘‘recurrence.’’ Randomized control studies
reporting on colorectal adenoma recurrence and folic acid supplementation
of at least 1 mg/day were selected. Studies were excluded if supplementation
was combined with other vitamins or pharmaceutical drugs.
RESULTS: Out of the 4013 records retrieved, 4 articles met the
inclusion criteria. Three of the studies were conducted in the United
States either during, or overlapping with, mandatory folate fortification.
Three of the studies supplemented with 1 mg/day for up to 6 years.
The remaining study used 5 mg/day for three years. The reported risk
ratio of colorectal adenoma recurrence with 1 mg/day after one year
was 0.60 (CI 95% 0.27-1.33), after 3 years, 1.20 (CI 95% 0.95-1.51)
and 0.82 (CI 95% 0.59-1.13). A risk ratio was not reported after 5 mg/
day for 3 years, rather the risk was described as “twice as high in the
placebo group versus the folic acid group.”
CONCLUSION: Supplementation of folic acid at either 1 mg/day
or 5 mg/day for a period of three years in an environment of mandatory
folate fortification did not increase nor decrease the risk of colorectal
adenoma recurrence in those individuals with a previous history of
colorectal adenomas. Pregnant women, at higher risk for neural tube
defects or other folate-dependent malformations, who may need a high
daily dose of folate (up to 5 mg/day) can use these doses safely for the
short period of first trimester of pregnancy.
PI-16
HIGH RISK PRESCRIBING AND INCIDENCE OF FRAILTY
AMONG OLDER COMMUNITY-DWELLING MEN. D. Gnjidic, 1 S.
N. Hilmer, 1 D. G. Le Couteur, 2 D. R. Abernethy 3 ; 1 Royal North Shore
Hospital and University of Sydney, Sydney, Australia, 2 Centre for Education
and Research on Ageing (CERA) and University of Sydney,
Sydney, Australia, 3 Food and Drug Administration, Silver Spring, MD.
D. Gnjidic: None. S.N. Hilmer: 4. I hold a patent for; Company/
Drug; Drug Burden Index. D.G. Le Couteur: None. D.R. Abernethy:
4. I hold a patent for; Company/Drug; Drug Burden Index.
BACKGROUND: Evidence on the association between treatment
with high risk medicines and frailty in older adults is limited. We aimed
to investigate the relationship between high risk prescribing and frailty
at baseline, and 2-year incident frailty in older adults.
METHODS: A total of 1662 community-dwelling males, aged ≥70
years enrolled in the Concord Health and Ageing in Men Project were
studied. Measurements were obtained at baseline (2005-2007) and
2-year follow-up (2007-2009). High risk prescribing was defined as
polypharmacy (use of ≥ 5 medicines), hyperpolypharmacy (use of ≥ 10
medicines) and by the Drug Burden Index (DBI), a dose-normalized
measure of anticholinergic and sedative medicines. Frailty was defined
according to validated criteria. Odds ratios of frailty were modeled
using logistic regression, and adjusted for age, education, marital status
and multiple comorbidities.
RESULTS: There were 9.4% participants who were identified as
frail at baseline. At baseline, frail participants had adjusted odds ratios
(ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy,
5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy and
2.33 (95%CI: 1.58-3.45) for DBI exposure, compared with non-frail.
Among the 1242 men who were non-frail at baseline, 6.2% developed
frailty over two years. Adjusted ORs of incident frailty were 2.45
(95%CI: 1.42-4.23) for polypharmacy, 2.50 (95%CI: 0.76-8.26) for
hyperpolypharmacy, and 2.14 (95%CI: 1.25-3.64) for DBI exposure.
CONCLUSION: Older frail men were significantly more likely to
be exposed to high risk prescribing than non-frail older men at baseline,
and exposure to high risk medicines was significantly related to
the development of frailty over two years.
PI-17
POLYPHARMACY AND ADVERSE OUTCOMES: DETER-
MINING THE BEST CUT-OFF FOR POLYPHARMACY
ASSOCIATED WITH GERIATRIC SYNDROMES, FUNC-
TIONAL OUTCOMES AND MORTALITY IN OLDER ADULTS.
D. Gnjidic, 1 D. G. Le Couteur, 2 S. N. Hilmer 1 ; 1 Royal North Shore
Hospital and University of Sydney, Sydney, Australia, 2 Centre
for Education and Research on Ageing (CERA) and University of
Sydney, Sydney, Australia. D. Gnjidic: None. D.G. Le Couteur:
None. S.N. Hilmer: None.
BACKGROUND: There is lack of agreement about the best cut-off
value for the number of concomitant medications that should be used
to define polypharmacy. We aimed to determine an optimal discriminating
number of concomitant medications for the associations with
adverse outcomes in older adults.
METHODS: Males aged ≥ 70 years (n=1705), participating in
the Concord Health and Ageing in Men Project were studied. Measurements
were obtained at baseline (2005-2007) and follow-up
assessments. Frailty was ascertained according to the validated criteria.
Disability was assessed using the Activities of Daily Living
scale. Participants were categorized as cognitively impaired (mildcognitive-impairment
or dementia) using clinical diagnostic criteria.
Prospective data on mortality and incident falls were collected
by 4-monthly telephone calls. Receiver operating characteristics
curve analysis using the Youden Index and the area under curve was
performed to determine discriminating number of medications in
relation to each outcome. Odds ratios were calculated for the association
of the number of concomitant medications with each of the
outcomes.
RESULTS: The highest value of the Youden Index for frailty was
obtained for a cut-off point of 6.5 medications, compared to a cut-off
of 5.5 for disability and 3.5 for cognitive impairment. For mortality
and falls, the highest value of Youden Index was obtained for a cut-off
of 4.5 medications. For every one increase in number of medications,
the adjusted odds ratios for age and multiple comorbidities, were 1.13
(95% confidence interval (CI): 1.06-1.21) for frailty, 1.08 (95%CI:
1.00-1.15) for disability, 1.02 (95%CI: 0.96-1.09) for cognitive impairment,
1.09 (95%CI: 1.04-1.15) for mortality and 1.07 (95%CI: 1.03-
1.12) for falls.
CONCLUSION: This study justifies the widespread definition of
polypharmacy, which is linked to adverse outcomes, as five or more
medications.
PI-18
A REVIEW OF FOOD AND DRUG ADMINISTRATION (FDA)
LABELING FOR OVERDOSE TREATMENT AND TOXICITY
DATA. M. E. Mazer, 1 G. Sokol, 2 L. Cantilena 2 ; 1 George Washington
University, Washington, DC, 2 Uniformed Services University of the
Health Sciences, Division of Clinical Pharmacology, Bethesda, MD.
M.E. Mazer: None. G. Sokol: None. L. Cantilena: None.
BACKGROUND: Adverse drug reactions, including overdose, are
a major cause of morbidity and mortality. The goal of the FDA is to
ensure approved pharmaceuticals are safe and effective yet clinical
toxicology data is often limited at the time of approval. There may also
be a lag time until toxicology data is available and incorporated into
labeling revisions. In order to determine the type and quality of clini-
s14 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
cal toxicology data available for newly approved pharmaceuticals and
time to labeling revisions, we reviewed the labeling data of 100 new
molecular entities (NMEs).
METHODS: Labeling information from the FDA database (www.
fda.gov) for 100 NMEs was examined, from December 2005 to July
2011. Initial approval data and subsequent labeling revisions were
reviewed. Data extracted included clinical toxicology data at initial
approval, labeling revisions with updated toxicology data, time to
update, and type of data added. Risk Evaluation and Mitigation Strategies
(REMS) labeling and black box warnings were noted.
RESULTS: Of the 100 NMEs reviewed, 27 had agent-specific
toxicology data in the labeling at the time of approval. General recommendations
for overdose management were made in 45 cases. Eight
pharmaceuticals reviewed had toxicology updates during the study
period. The average time to labeling revision was 27.4 months (range
12-52, median 32). Expanded adverse effects from case reports comprised
7/8 of the updates and animal data was added in 1 case. There
were 12 agents approved with REMS status and 29 with black box
warnings.
CONCLUSION: Our study suggests there is a paucity of clinical
toxicology data at the time of drug approval. Over a third of the NMEs
had a black box warning or REMS status, suggesting potential for
significant human toxicity. A notable lag time between initial approval
and labeling revisions was seen. This essential lack of toxicology data
limits the ability of providers to optimally care for poisoned patients
and warrants further investigation.
PI-19
AN IN VIVO HUMAN TIME-EXPOSURE INVESTIGATION OF
A COMMERCIAL SILVER NANO-PARTICLE SOLUTION. M. A.
Munger, P. Radwanski, G. J. Stoddard, A. Shaaban, D. Grainger, G.
Yost; Univ of Utah, SLC, UT. M.A. Munger: None. P. Radwanski:
None. G.J. Stoddard: None. A. Shaaban: None. D. Grainger: None.
G. Yost: None.
BACKGROUND: The biodistribution, bioprocessing and possible
toxicity of silver nanoparticles is receiving increasing attention in
human health through greater exposures.
METHODS: To understand whether these concerns are justified,
we prospectively studied 3-, 7-, and 14-day exposures to an American
Biotech Laboratory 10-ppm (15 ml/day) silver solution in a doubleblind,
controlled, cross-over phase design. Healthy volunteer subjects
(36, 12 each time-exposure), underwent complete metabolic, blood
and platelet count, urinalysis tests, sputum hyperresponsiveness and
inflammation evaluation, physical examinations, vital sign measurements,
and magnetic resonance imaging of the chest and abdomen at
baseline and end of each phase. Diet was not controlled. Silver serum
and urine quantization was determined by inductively coupled plasma
mass spectrometry (NMS Labs). Significance in individual laboratory
values was determined by any value being 2 x ULN or 4 SD from
the mean and by clinical judgment. Mixed effects linear and logistic
regression models compared the mean effect to the normal reference
range control limits. MRI morphology changes were qualitatively
described.
RESULTS: No clinically important changes in any metabolic,
hematologic, or urinalysis measure identified were determined. No
morphological (or structural) changes were detected in the lungs, heart
(cardiac function) or abdominal organs. No changes were noted in sputum
reactive oxygen species or in pro-inflammatory cytokines.
CONCLUSION: In-vivo oral exposure of a commercial 10-ppm
silver nano-particle solution over 3-, 7-, and 14-day exposures does
not exhibit clinically important changes in metabolic, hematologic,
urine, vital sign changes, physical findings or imaging changes visualized
by MRI. Further study of increasing time-exposure, dose, and
additional organ systems, including cytochrome P-450 enzymes, is
warranted.
aBsTraCTs
PI-20
CAPILLARY ELECTROPHORESIS-LASER INDUCED FLU-
ORESCENCE (CE-LIF) ASSAY FOR MEASUREMENT OF
INTRA-CELLULAR D-SERINE AND SERINE RACEMASE
ACTIVITY. N. S. Singh, R. K. Paul, M. Sichler, R. Moaddel,
M. Bernier, I. W. Wainer, A. Ramamoorthy; National Institute
on Aging/NIH, Baltimore, MD. N.S. Singh: None. R.K. Paul:
None. M. Sichler: None. R. Moaddel: None. M. Bernier: None.
I.W. Wainer: None. A. Ramamoorthy: None.
BACKGROUND: D-Serine (D-Ser) is an NMDAR co-agonist generated
by serine racemase (SR). Changes in endogenous D-Ser levels
have been associated with CNS disorders; decreased levels with schizophrenia
and increased levels linked to Alzheimer’s disease. These
observations led to therapeutic approaches which either augment
D-Ser levels by or decrease SR activity.
METHODS: An enantioselective capillary electrophoresis-laser
induced fluorescence (CE-LIF) method for quantification of intracellular
D-Ser levels was developed for the determination of changes
in SR activity. The assay involves derivatization with FITC followed
by CE-LIF using hydroxyl propyl-β-cyclodextrin as the chiral selector.
The method was applied to the determination of intra-cellular
D-Ser concentrations in PC-12, C6, 1312N1 and HepG2 cell lines and
concentration-dependent changes in D-Ser produced by L-Ser and
gycine, a SR competitive inhibitor. Western blot analysis was used to
determine SR expression.
RESULTS: The CE-LIF method resolved D-Ser and L-Ser with
an enantioselectivity of 1.05 and Resolution of 1.65. EC50 values for
L-Ser ranged from 5.41 ± 0.76 mM (PC-12) to 9.37 ± 0.17 mM (C6)
and IC50 values for the Gly ranged from 0.68 ± 0.15 mM (C6) to 1.83
± 0.07 mM (HepG2). Western blot analysis determined that the PC-12
and C6 cell lines expressed monomeric and dimeric forms of SR while
the 1321N1 and HepG2 cells contained only the monomeric form.
Although the SR dimer has been identified as the active form of the
enzyme, all four cell lines were enzymatically active.
CONCLUSION: The data from this study indicate that the CE-LIF
assay developed in this project can be used to assess changes in intracellular
D-Ser concentrations. However, the results also demonstrate
that this technique should be combined with Western blot analysis to
obtain an accurate picture of the effect on SR activity.
PI-21
KETAMINE AND METABOLITES SUBTYPE SELECTIVITY IN
THE NICOTINIC RECEPTOR FAMILY. R. Moaddel, 1 A. Rosenberg, 1
G. Abdrakhmanova, 2 K. Jozwiak, 3 A. Ramamoorthy, 1 I. W. Wainer 1 ;
1 NIA/NIH, Baltimore, MD, 2 Virginia Commonwealth University, Richmond,
VA, 3 Medical University of Lublin, Lublin, Poland. R. Moaddel:
None. A. Rosenberg: None. G. Abdrakhmanova: None. K. Jozwiak:
None. A. Ramamoorthy: None. I.W. Wainer: None.
BACKGROUND: Ketamine (K), effective in both depression and
chronic pain, is administered as a racemic mixture and is extensively
metabolized to norketamine (NK), dehydronorketamine (DHNK),
hydroxynorketamines (HNK) and hydroxyketamines (HK). While the
pharmacological activities of K and NK have been characterized, little
is known about the activities of the other metabolites. We have investigated
the activity of DHNK, HNK and HK at the α 7 and α 3 β 4 nicotinic
receptors (NR).
METHODS: Patch-clamp techniques were used to examine
functional activity of K metabolites at 100 nM on α 7 and α 3 β 4 . The
functional activity of these compounds at the α 3 β 4 NR was investigated
using nicotine-stimulated 86 Rb + efflux assays in HEK293 cells
expressing the α 3 β 4 NR.
RESULTS: In the α 7 NR, DHNK was the most potent producing a
60% inhibition, followed by NK. The metabolites did not exhibit agonist
activity by patch clamp for either subtype. The data from the nicotine-stimulated
86 Rb + efflux studies demonstrated that K metabolites
partially stimulated the α 3 β 4 NR at sub-μM concentrations and that this
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aBsTraCTs nature publishing group
effect was lost at a concentration of 1 μM, with only K demonstrating the
significant inhibition of efflux, which was confirmed by patch-clamp.
CONCLUSION: The data demonstrate that the K metabolites
partially (40% relative to nicotine) stimulated the α3β4 NR at 100 nM
concentrations and this effect was lost at higher concentrations. The
observed stimulation was inhibited by the NR antagonist mecamylamine
indicating that this was mediated by NR. In addition, the inhibition of
Rb efflux was only seen for K, with weak inhibition by NK, HK1 and
HNK. While for the α7 NR, weak inhibition was observed for all metabolites
except DHNK, which had a pronounced effect, suggesting subtype
selectivity for K and DHNK for NR. The variability observed in treatment
response in depressed patients and chronic pain patients may be
due to individual differences in the metabolism of K.
PI-22
HYPERTENSION SUSCEPTIBILITY LOCI ASSOCIATED
WITH BLOOD PRESSURE RESPONSE TO ANTIHYPERTEN-
SIVES- RESULTS FROM THE PHARMACOGENOMIC EVALU-
ATION OF ANTIHYPERTENSIVE RESPONSES (PEAR) STUDY.
Y. Gong, 1 C. W. McDonough, 1 Z. Wang, 2 R. M. Cooper-DeHoff, 1
T. Y. Langaee, 1 A. L. Beitelshee, 3 S. T. Turner, 4 A. B. Chapman, 5
J. G. Gums, 1 K. R. Bailey, 4 E. Boerwinkle, 2 J. A. Johnson 1 ; 1 University
of Florida, Gainesville, FL, 2 University of Texas, Houston, TX,
3 University of Maryland, Baltimore, MD, 4 Mayo Clinic, Rochester,
MN, 5 Emory University, Atlanta, GA. Y. Gong: 1. This research
was sponsored by; Company/Drug; NIH grant U01 GM074492.
C.W. McDonough: None. Z. Wang: None. R.M. Cooper-DeHoff:
1. This research was sponsored by; Company/Drug; NIH grant U01
GM074492, HL084090. T.Y. Langaee: 1. This research was sponsored
by; Company/Drug; NIH grant U01 GM074492. A.L. Beitelshee:
1. This research was sponsored by; Company/Drug; NIH grant
U01 GM074492. S.T. Turner: 1. This research was sponsored by;
Company/Drug; NIH grant U01 GM074492. A.B. Chapman: 1.
This research was sponsored by; Company/Drug; NIH grant U01
GM074492. J.G. Gums: 1. This research was sponsored by; Company/Drug;
NIH grant U01 GM074492. K.R. Bailey: 1. This research
was sponsored by; Company/Drug; NIH grant U01 GM074492. E.
Boerwinkle: 1. This research was sponsored by; Company/Drug; NIH
grant U01 GM074492. J.A. Johnson: 1. This research was sponsored
by; Company/Drug; NIH grant U01 GM074492. 2. I am a paid consultant/employee
for; Company/Drug; Medco.
BACKGROUND: To date, 39 SNPs are associated with blood pressure
(BP) in genome-wide association studies (GWAS) in whites. We
assessed the association of these loci with BP response to atenolol
(ATEN) and hydrochlorothiazide (HCTZ), with particular interest in
loci with opposite associations for the two drugs, given their contrasting
pharmacological mechanisms.
METHODS: PEAR evaluated BP response in 768 hypertensive
patients randomized to either ATEN or HCTZ monotherapy then the
combination. Genotypes of 37 loci were obtained from Illumina 50K
cardiovascular or Omni1M GWAS chips. Associations with systolic
(SBP) and diastolic BP (DBP) responses to ATEN or HCTZ mono-
or add-on therapy was evaluated in 464 white individuals using linear
regression adjusting for baseline BP, age, gender and principal components
for ancestry.
RESULTS: Eight SNPs reached nominal significance (p

nature publishing group
PI-24
HEME OXYGENASE-1 (HO-1) IS A POSSIBLE MEDIATOR OF
CYTOPROTECTIVE EFFECTS BY N-ACETYLCYSTEINE (NAC)
IN CHILDHOOD CEREBRAL ADRENOLEUKODYSTROPHY
(CCALD) PATIENTS. J. Zhou*, R. V. Kartha*, L. Basso, P. J. Orchard,
H. Schroder, J. C. Cloyd; University of Minnesota, Minneapolis, MN.
J. Zhou*: None. R.V. Kartha*: None. L. Basso: None. P.J. Orchard:
None. H. Schroder: None. J.C. Cloyd: None.
BACKGROUND: N-acetylcysteine (NAC), an antioxidant indicated
for treating acetaminophen overdose, is used as adjunctive
therapy along with hematopoietic cell transplantation (HCT) in latestage
CCALD, an inherited demyelinating disorder. Use of NAC with
HCT enhances survival, but the underlying mechanism is unknown.
Hemeoxygenase-1 (HO-1) and ferritin are known to mediate cytoprotective
and antioxidant effects of various drugs. This study investigates
whether HO-1 and ferritin are potential mediators of NAC in CCALD
patients and oligodendrocytes. These findings may help optimize therapy
in both early and late-stage CCALD.
METHODS: Subjects in this study were CCALD patients scheduled
to undergo HCT. NAC was given as IV at 70mg/kg every 6hr
for 4 days following admission but prior to pre-HCT chemotherapy.
Plasma was obtained from 5 patients and expression of HO-1 (Assay
Designs) and ferritin (Abnova) determined by ELISA. In vitro assays
were performed in myelin forming murine oligodendrocytes (158N).
Oxidative stress was induced by incubating cells with 500μM H2O2
for 24hr. NAC was used at 50-500μM concentration. Reactive Oxygen
Species (ROS) formation and cell viability were determined by flow
cytometry and colorimetric assays, respectively.
RESULTS: Following NAC therapy, plasma HO-1 and ferritin were
significantly induced (p

aBsTraCTs nature publishing group
PI-27
PROGRESSIVE DECLINE IN IN VIVO CYP3A4-ACTIVITY
EXPLAINS TIME-RELATED INCREASE IN DOSE CORRECTED
TACROLIMUS EXPOSURE AFTER RENAL TRANSPLANTA-
TION. H. de Jonge, 1 H. de Loor, 1 K. Verbeke, 2 Y. Vanrenterghem, 1
D. R. Kuypers1 ; 1Department of Nephrology and Renal Transplantation,
University Hospitals Leuven, Leuven, Belgium, 2Department of Gastrointestinal Research, Catholic University Leuven, Leuven,
Belgium. H. de Jonge: None. H. de Loor: None. K. Verbeke: None.
Y. Vanrenterghem: None. D.R. Kuypers: None.
BACKGROUND: Tacrolimus (Tac) is metabolized by CYP3A4
and 3A5. Its long-term disposition following transplantation (Tx) is
characterized by a gradual increase in dose corrected exposure. The
latter has been attributed to declining CYP3A4 activity, but this has
never been demonstrated in an in vivo setting.
METHODS: One year longitudinal follow-up study in 65 Tac
treated renal recipients tested 7 days and 1, 3, 6 and 12 months
after Tx. At all time-points in vivo CYP3A4 activity (using PO and
IV midazolam (MDZ) as drug probe) and Tac PK (using dose-interval
AUC) were assessed. Data were analyzed using linear mixed models.
RESULTS: In the first year after kidney Tx apparent oral MDZ
clearance (MDZ Cl/F, Fig), systemic MDZ clearance and Tac dose
requirements progressively decreased, while dose corrected Tac AUC0- 12 gradually increased (Fig) (p

nature publishing group
BACKGROUND: CYP450-mediated drug metabolism in extrahepatic
tissues may contribute to the local disposition of drugs. CYP2E1
metabolism in cardiac tissue may be clinically relevant as it is one of
the most abundant isoenzymes (mRNA) found in the human heart. We
therefore characterized CYP2E1 activity in human heart microsomes
using the probe drug chlorzoxazone (CZX).
METHODS: CZX was incubated with freshly isolated human heart
microsomes (left ventricle) and with recombinant CYP2E1 (Supersome;
BD Gentest). The incubation contained 100 mM phosphate
buffer, NADPH regenerating system (glucose-6-phosphate, NADP
and glucose-6-phosphate dehydrogenase), CZX (0 to 1,500 μM) and
microsomes. Reaction was stopped with ice-cold acidified MeOH
(100 mM HCl) with the internal standard. Liquid-liquid extraction
was performed with MTBE. The organic phase was evaporated to dryness
under a stream of nitrogen, resolubilized in 100 mM HCl MeOH.
HPLC-UV was used to quantify the formation of 6-hydroxychlorzoxazone
(6-OHCZX). mRNA relative expression of CYP1A1 and 2E1
was quantified by real-time PCR.
RESULTS: Michaelis-Menten kinetics was used to determine the
intrinsic clearance (Clint), Vmax and Km parameters in both systems.
Clint was 0,0013 mL/min (Km = 211 μM, Vmax = 7,680 pmol/mg
of protein/min) in the rCYP2E1. On the other hand, Clint was 9,2 x
10 -06 mL/min (Km = 6,083 μM, Vmax = 1192 pmol/mg of protein/
min) in human heart microsomes. Other CYP450s involved in the
CZX metabolism could explain the lower intrinsic clearance observed
in the human heart microsomes. Accordingly, we have observed that
rCYP1A1 can also metabolize CZX (reaction rate is ≈60% of that
measured for CYP2E1). Since CYP1A1 mRNA is 10 times more
expressed than CYP2E1 in this heart the contribution of CYP1A1 must
be considered for the kinetics of CZX.
CONCLUSION: In a human heart expressing CYP2E1, metabolic
activity was observed. This is the first characterization of human heart
CYP450 2E1-mediated metabolism.
PI-31
CYP450 FUNCTIONAL ACTIVITIES IN HUMAN HEART
MICROSOMES. J. Huguet, 1 V. Michaud, 2 F. Gaudette, 3 J. Turgeon
4 ; 1 University of Montreal - CRCHUIM, Montreal, QC, Canada,
2 University of Indianapolis, Indianapolis, IN, 3 CRCHUM, Montreal,
QC, Canada, 4 University of Montreal - CRCHUM, Montreal, QC,
Canada. J. Huguet: None. V. Michaud: None. F. Gaudette: None.
J. Turgeon: None.
BACKGROUND: Extrahepatic CYP450s may contribute significantly
to the local metabolism of drugs. For the first time, we have
used a cocktail of probe drugs to characterize CYP2J2, CYP2C9 and
CYP2B6 functional activities in human heart microsomes (HHM).
METHODS: Ebastine (CYP2J2; 0 to 33 μM), bupropion (CYP2B6;
0 to 1.546 mM) and tolbutamide (CYP2C9; 0 to 1.5 mM) constituted
the substrate cocktail. A first set of experiments was conducted with
recombinant CYP450 isozymes (Supersome) and substrates incubated
separately, and together, to identify potential competitive inhibition.
Then, incubations were performed with freshly isolated HHM and
the substrate cocktail. Reactions were stopped with ice-cold MeOH
(containing the internal standard). Incubations were centrifuged at
12 000 rpm, and the supernatant analyzed by LC-MS.
RESULTS: Intrinsic clearance (Clint) for ebastine hydroxylation
in Supersomes2J2 was 0,0128 and 0,0203 mL/min when incubated
alone or with the cocktail, respectively, compared to 7,2 X 10 -3 mL/
min in the HHM. Presence of other CYP450s in the HHM could influence
the selectivity of each CYP450 toward probe drug metabolism
which could explain the lower Clint in HHM compared to the Supersomes.
Activities measured in HHM for ebastine, bupropion, and
tolbutamide correlated well with mRNA levels measured for CYP2J2,
CYP2B6 and CYP2C9, respectively.
CONCLUSIONS: Human heart microsomes express significant
levels of CP450 isozymes which may contribute to the local metabolism
of drugs.
aBsTraCTs
Michaelis-Menten Kinetics Parameters
Alone in
Cocktail
Cocktail Cocktail
Alone in
Super- Cocktail in Super- Cocktail in HHM in HHM
Supersomes
in Supersomes in HHM Vmax Velocity at isoen-
Subs trates omes
Vmax somes Vmax (pmol/ Km (pmol/ 3 times Km zymes
Km
(pmol/mg Km (µM) mg prot/ (µM) mg prot/ (pmol/mg
(µM)
prot/min)
min)
min) prot/min)
mRNA
relative
expression
Ebas tine 5,2 5905 2,6 4693 0,52 82 72 CYP2J2 4,4X105 Tolbutamide 111 2989 - - 379 2,17 1,69 CYP2B6 20
Bupro pion 160 1819 - - - - 0,25 CYP2C9 1
PI-32
STEREOSELECTIVE CONJUGATION OF 4-METHOXY-
FENOTEROL STEREOISOMERS BY SULFOTRANSFERASES.
L. V. Iyer, 1 A. Ramamoorthy, 2 A. M. Furimsky, 1 L. Tang, 1 P. Catz, 1
C. E. Green, 1 I. W. Wainer 2 ; 1 SRI International, Menlo Park, CA,
2 National Institute on Aging, Baltimore, MD. L.V. Iyer: None.
A. Ramamoorthy: None. A.M. Furimsky: None. L. Tang: None.
P. Catz: None. C.E. Green: None. I.W. Wainer: None.
BACKGROUND: 4-Methoxyfenoterol (MF), a potent ß 2 agonist,
is a chiral molecule with four possible stereoisomers (R,R-, S,S-, R,S-,
and S,R-MF). It is an analog of fenoterol (FEN) which is in initial
clinical trials for use in congestive heart failure but has a poor bioavailability
due to extensive presystemic sulfation or glucuronidation.
The 4’-methoxyphenyl group in MF may reduce the sites available for
phase II conjugation and hence MF may have a better pharmacokinetic
profile than FEN. The current study was performed to investigate i)
the sulfation of MF stereoisomers and ii) the sulfation of R,R-MF in
combination with each other MF isomer.
METHODS: MF isomers were incubated with human intestinal
S9 and cDNA expressed human SULT isoforms (SULT1A1, 1A1*2,
1A2, 1A3, 1B1, 1C2, 1E1, 2A1). Competition experiments were
performed to study the sulfation of [ 3 H]-R,R-MF in presence of the
other MF isomers. MF isomers and sulfates were identified using an
LC-MS/MS method or HPLC with radiochemical detection.
RESULTS: Sulfation of all four MF isomers followed Michaelis
Menten kinetics (r 2 ≥ 0.99). Individual K m values were ~ 62 μM
(R,R-MF), 89 μM (S,S-MF), 69 μM (R,S-MF), 52 μM (S,R-MF). The
maximal formation of R,R-MF- and R,S-MF sulfates was about 50%
lower than that of S,S-MF and S,R-MF. SULT1A1*1, 1A1*2, 1A3 and
1E1 were capable of sulfation of all four MF isomers. Coincubation of
S,R-MF resulted in a significant (p200 μM.
CONCLUSION: The results indicate that the sulfation of MF is
stereoselective in terms of the formation rate of sulfates of isomers.
Specific human SULTs were responsible for sulfation of MF isomers.
The inhibition of sulfation of R,R-MF by S,R-MF might be an interesting
strategy to improve the bioavailability and pharmacokinetic properties
of R,R-MF.
Funded by NIA (HHSN271201000008I).
PI-33
DEXMEDETOMIDINE DECREASES SERUM INSU-
LIN CONCENTRATIONS AND THIS RESPONSE IS INFLU-
ENCED BY ALPHA2A ADRENOCEPTOR GENETIC
VARIATION. L. V. Ghimire, 1 D. Kurnik, 1 M. Muszkat, 1 G. G. Sofowora,
1 M. Scheinin, 2 A. J. Wood, 1 C. Stein 1 ; 1 Vanderbilt University,
Nashville, TN, 2 University of Turku, Turku, Finland. L.V. Ghimire:
None. D. Kurnik: None. M. Muszkat: None. G.G. Sofowora: None.
M. Scheinin: 2. I am a paid consultant/employee for; Company/Drug;
Dr. Scheinin has received speaker fees and consulting fees from Orion
Corporation. A.J. Wood: None. C. Stein: None.
BACKGROUND: Sympathetic activation inhibits insulin secretion
through pancreatic alpha2A-adrenoceptors (α2AARs). A common
α2AAR genetic variant (rs553668) is associated with impaired insulin
secretion. We tested the hypothesis that dexmedetomidine (DEX), a
selective α2AR agonist widely used in intensive care, decreases insulin
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aBsTraCTs nature publishing group
and increases glucose levels in humans, and that ADRA2A variation
modifies these effects.
METHODS: Healthy Caucasians (n=28) and African-Americans
(n=32), aged 18-45 years, received 3 sequential infusions of placebo
at 30 minute intervals followed by 3 infusions of DEX (0.1, 0.15, and
0.15 mcg/kg). We measured serum insulin and glucose concentrations
and genotyped for ADRA2A rs553668 and rs2484516 that characterize
haplotypes 4 and 4b, respectively.
RESULTS: DEX decreased insulin concentrations by 27% from
8.4±6.1 μU/mL to 6.1±3.9 μU/mL (P

nature publishing group
Top nsSNPs associated with Primary Outcome
Based on Treatment Interaction,
Analysis Presented as Risk of Event within Treatment Arm,
Under an Additive Genetic Model.
White (n=795). Hispanic (Hisp, n=380)
White SELE Ser149Arg CCB
White SELE Ser149Arg BB
Hisp SELP Val209Met CCB
Hisp SELP Val209Met BB
White SIGLEC12 Gln29stop CCB
White SIGLEC12 Gln29stop BB
Hisp SIGLEC12 Gln29stop CCB
Hisp SIGLEC12 Gln29stop BB
S149R Interaction P=0.048
V209M Interaction P=0.002
Q29stop Interaction P=0.033
Q29stop Interaction P=0.021
0 1 2 3 4 5 6 7 8
Odds Ratio and 95% Confidence Intervals
PI-36
ALPHA ADDUCIN-1 (ADD1) SINGLE NUCLEOTIDE POLYMOR-
PHISM (SNP) ASSOCIATED WITH NEW ONSET DIABETES RISK
WITH HYDROCHLOROTHIAZIDE (HCTZ) THERAPY IN THE
INTERNATIONAL VERAPAMIL SR TRANDOLAPRIL GENETIC
SUBSTUDY (INVEST-GENES). J. H. Karnes, C. W. McDonough, Y.
Gong, T. Y. Langaee, C. J. Pepine, J. A. Johnson, R. M. Cooper-DeHoff;
University of Florida, Gainesville, FL. J.H. Karnes: 1. This research
was sponsored by; Company/ Drug; NIH Grant TL1RR029888. C.W.
McDonough: None. Y. Gong: 1. This research was sponsored by; Company/Drug;
NIH grants HL074730, HL69758, HL077113, GM074492
and RR017568, a grant from Abbott Pharmaceuticals and the Florida
Opportunity Fund. T.Y. Langaee: 1. This research was sponsored
by; Company/Drug; NIH grants HL074730, HL69758, HL077113,
GM074492 and RR017568, a grant from Abbott Pharmaceuticals
and the Florida Opportunity Fund. C.J. Pepine: 1. This research was
sponsored by; Company/Drug; NIH grants HL074730, HL69758,
HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals
and the Florida Opportunity Fund. 2. I am a paid consultant/
employee for; Company/Drug; Abbott Labs, Angioblast Systems,
Athersys, Baxter Healthcare, Boehringer Ingelheim, Gilead, Medtelligence,
NicOx, Pfizer, sanofi-aventis, Schering-Plough, Servier and
Slack. J.A. Johnson: 1. This research was sponsored by; Company/
Drug; NIH grants HL074730, HL69758, HL077113, GM074492 and
RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity
Fund. 2. I am a paid consultant/employee for; Company/Drug;
Medco. R.M. Cooper- DeHoff: 1. This research was sponsored by;
Company/Drug; NIH grants K23 HL086558, HL074730, HL69758,
HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals
and the Florida Opportunity Fund.
BACKGROUND: The first line antihypertensive HCTZ is associated
with increased new onset diabetes (NOD) risk. SNPs may help
identify patients at risk for HCTZ-induced NOD and guide prescribing
to reduce diabetes risk. The ADD1 SNP Gly460Trp has been associated
with increased NOD risk in thiazide treated patients. Our study
aimed to replicate this association and assess 31 additional ADD1
SNPs for NOD risk with HCTZ therapy in patients with hypertension
and coronary artery disease.
aBsTraCTs
METHODS: INVEST recorded cardiovascular outcomes and NOD
during a comparison of two antihypertensive strategies over a mean 2.8
years of follow up. A total of 446 NOD cases were identified and age,
race and sex matched to 1,025 controls. We determined odds ratios and
95% confidence intervals for NOD in HCTZ treated versus non HCTZ
treated patients using logistic regression by race/ethnicity. We calculated
SNP*HCTZ treatment interaction p values adjusted for false discovery
rate to determine pharmacogenetic effects.
RESULTS: Gly460Trp did not increase NOD risk in HCTZ treated
versus non HCTZ treated patients overall or in any race/ethnicity. The
rs3775067 C allele was associated with NOD in HCTZ treated versus non
HCTZ treated patients in whites, with a similar trend overall. (Figure 1)
CONCLUSION: We did not replicate the previous association of
Gly460Trp and thiazide induced NOD. However, the pharmacogenetic
effect of rs3775067 in INVEST whites suggests that ADD1 influences
HCTZ induced NOD. Replication of this association is needed.
Gly460Trp (rs4691)
Overall
Trp/Trp
Whites*
Trp carriers
rs3775067
Overall
C/C
Whites
C/C
SNP*HCTZ treatment
Interaction p value
PI-37
SULFONYLUREA RECEPTOR POLYMORPHISMS IN ABCC8
AFFECT THE RESPONSE TO SULFONYLUREA TREATMENT
IN PATIENTS WITH TYPE 2 DIABETES MELLITUS. J. A. Wessels,
J. J. Swen, T. Van der Straaten, T. El Hajoui, W. J. Assendelft, H. J.
Guchelaar; Leiden University Medical Centre, Leiden, Netherlands.
J.A. Wessels: None. J.J. Swen: None. T. Van der Straaten: None.
T. El Hajoui: None. W.J. Assendelft: None. H.J. Guchelaar: None.
BACKGROUND: There is significant interpatient variability
in response to sulfonylureas (SUs) in patients with Type 2 Diabetes Mellitus
(T2DM). We hypothesize that polymorphisms in the ABCC8 gene
encoding the sulfonylurea receptor 1 influence the response to SUs.
METHODS: Two hundred and seven incident SU users (tolbutamide,
glibenclamide, glimepiride, gliclazide) with T2DM were recruited from
four primary care centers. Retrospective medical and prescription data
were retrieved from the electronic patient record. Haplotype analysis of the
ABCC8 gene was performed by means of the fifteen most informative polymorphisms,
resulting in fourteen haplotypes defined in four blocks. The
association of these ABCC8 haplotypes with the achievement of stable SU
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s21
Gly/Trp
Gly/Gly
Gly/Trp
C/G
G/G
C/G
G/G
Decreased NOD
risk with HCTZ
p = 0.95
p = 0.60
p = 0.008
p FDR = 0.27
p = 0.002
pFDR = 0.04
0 1 2 3 4 5 6 14 15
Increased NOD risk
with HCTZ
Figure 1: Odds ratios and 95% confidence intervals for HCTZtreated
versus non HCTZ-treated patients by genotype group.
All statistics are adjusted for age, gender, body mass index, on
treatment systolic blood pressure, atenolol or trandolapril
treatment, and principal components one, two and three. HCTZ
indicates hydrochlorothiazide, NOD new onset diabetes
*Gly460Trp presented as Trp carriers due to low Trp frequency

aBsTraCTs nature publishing group
dose, prescribed stable SU dose, and time to stable SU dose was explored.
Stable SU dose was defined as the 1st period of ≥270 consecutive days
without dose adjustment, initiation of other SUs, insulin or metformin.
RESULTS: Carriers of the GTGGC haplotype had a 2.2-fold
increased likelihood to achieve stable SU dose (P = 0.024), while no
significant effect of the number of copies of this ABCC8 haplotype
on prescribed dose was found. Of the patients with two copies of the
GTGGC haplotype, 86% achieved stable SU dose, whereas of the
patients with one copy and no copy of the GTGGC haplotype 81%
and 66% achieved stable SU dose, respectively. Additionally, carriers
of the GTGGC haplotype also showed a significant decreased time to
stable dose (hazard ratio: 0.70; 95% confidence interval, 0.54-0.91, P=
0.006). No associations with any of the other haplotypes were found.
CONCLUSION: The sulfonylurea receptor GTGGC haplotype is
associated with response to SUs in primary care T2DM patients. This
suggests that individualization of T2DM treatment according to genetic
profile may be an opportunity to improve clinical outcome.
PI-38
PON-1 IS NOT THE MAJOR BIOACTIVATION PATHWAY OF
CLOPIDOGREL IN-VITRO. V. Ancrenaz, 1 J. Desmeules, 1 R. James, 2
P. Dayer, 1 Y. Daali 1 ; 1 Clinical Pharmacology Service, Geneva
University Hospitals, Geneva, Switzerland, 2 Geneva University
Hospitals, Geneva, Switzerland. V. Ancrenaz: None. J. Desmeules:
None. R. James: None. P. Dayer: None. Y. Daali: None.
BACKGROUND: Clopidogrel (CLP) is a prodrug bioactivated by
cytochromes P450 (CYPs). Recently paraoxonase-1 (PON-1) was designated
as the major enzyme involved in the bioactivation of CLP. The
purpose of this study was to assess the relative involvement of CYPs
and PON-1 in the CLP metabolism in vitro.
METHODS: PON-1 activity was measured in serum and human
liver microsomes (HLMs) using phenyalacetate and serum activity
was adjusted to HLMs activity. CLP metabolism was studied in human
serum, in recombinant PON-1 enzyme (rePON1), pooled HLMs and
in HLMs with CYP2C19*1/*1 and CYP2C19*2/*2 genotypes. Inhibition
studies were also performed using specific CYP inhibitors or CYPs
and PON-1 antibodies. CLP active metabolite (CLP-AM) was measured
using an LC-MS-MS method after derivatization with 2-bromo-3’methoxyacetophenone.
RESULTS: PON-1 activity (mean±SD) was found to be 294.9±28.5
U/ml, 2.01±0.1 U/mg, 1.99±0.04 U/mg and 2±0.04 U/mg in human
serum, pooled HLMs, CYP2C19*1/*1 HLM and CYP2C19*2/*2
HLMs, respectively. Production of CLP-AM from 2oxo-CLP was
around 500 fold lower in human serum than in pooled HLMs. When
2oxo-CLP was incubated with rePON1 (from 0 to 100 μg), CLP-AM
could not be detected. CLP-AM production from 2oxo-CLP was lower
in HLMs with CYP2C19*2/*2 genotype (V max =18.4 ±0.96 pmol/min/
mg) compared to HLMs with *1/*1 genotype (V max =4.1±0.08 pmol/
min/mg) while PON-1 activity was similar in the two microsomes.
Moreover, incubations in the presence specific inhibitors of CYP3A,
CYP2B6 and CYP2C19 significantly reduced CLP bioactivation while
EDTA, the PON-1 specific inhibitor had only a weak inhibitory effect.
CONCLUSION: CYP2C19 genetic polymorphism played an
important role in the bioactivation of CLP in vitro. CYP3A and
CYP2B6 inhibition with ritonavir significantly reduced the production
of the CLP-AM. PON-1 is not involved in the metabolism of clopidogrel
at clinically relevant concentrations.
PI-39
MULTIPLE DOSES (MD) OF RIDAFOROLIMUS (RIDA) DO
NOT HAVE A CLINICALLY IMPORTANT IMPACT ON THE
SINGLE DOSE (SD) PHARMACOKINETICS (PK) OF MIDA-
ZOLAM (MDZ). A. Patnaik, 1 A. Tolcher, 1 J. E. Talaty, 2 M. A.
Stroh, 3 J. B. McCrea, 2 M. Trucksis, 4 J. Palcza, 5 K. Orford, 6 K. Cerchio,
2 S. Breidinger, 7 D. Panebianco, 5 J. A. Wagner, 8 N. Agrawal, 7
G. Carrizales, 1 R. Lush, 9 K. Papadopoulos 1 ; 1 South Texas Accelerated
Research Therapeutics, San Antonio, TX, 2 Clinical Phar-
macology, Merck & Co., Inc., North Wales, PA, 3 At the time of the
study, Dr. Stroh was in Clinical PK/PD, Merck & Co., Inc., West
Point, PA, 4 Clinical Pharmacology, Merck & Co., Inc., Boston,
PA, 5 BARDS, Merck & Co., Inc., North Wales, PA, 6 At the time of
the study, Dr. Orford was in Clinical Pharmacology, Merck & Co.,
Inc., North Wales, PA, 7 Clinical PK/PD, Merck & Co., Inc., West
Point, PA, 8 Clinical Pharmacology, Merck & Co., Inc., Rahway, NJ,
9 H. Lee Moffit Cancer Center and Research Institute, Tampa, FL.
A. Patnaik: 1. This research was sponsored by; Company/Drug;
Merck & Co., Inc./Ridaforolimus. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the
product is still investigational; Company/Drug; Merck & Co., Inc./
Ridaforolimus. A. Tolcher: 1. This research was sponsored by; Company/Drug;
Merck & Co., Inc/Ridaforolimus. J.E. Talaty: 2. I am a
paid consultant/employee for; Company/ Drug; Merck & Co., Inc./
Ridaforolimus. M.A. Stroh: 2. I am a paid consultant/employee for;
Company/Drug; Merck & Co., Inc./Ridaforolimus. J.B. McCrea: 2.
I am a paid consultant/employee for; Company/Drug; Merck & Co.,
Inc./Ridaforolimus. M. Trucksis: 2. I am a paid consultant/employee
for; Company/Drug; Merck & Co., Inc./Ridaforolimus. J. Palcza: 2.
I am a paid consultant/employee for; Company/Drug; Merck & Co.,
Inc./Ridaforolimus. K. Orford: 2. I am a paid consultant/employee for;
Company/Drug; Merck & Co., Inc./Ridaforolimus. K. Cerchio: 2. I
am a paid consultant/employee for; Company/Drug; Merck & Co.,
Inc./Ridaforolimus. S. Breidinger: 2. I am a paid consultant/employee
for; Company/Drug; Merck & Co., Inc./Ridaforolimus. D. Panebianco:
2. I am a paid consultant/employee for; Company/Drug; Merck
& Co., Inc./Ridaforolimus. J.A. Wagner: 2. I am a paid consultant/
employee for; Company/Drug; Merck & Co., Inc./ Ridaforolimus. N.
Agrawal: 2. I am a paid consultant/employee for; Company/Drug;
Merck & Co., Inc./Ridaforolimus. G. Carrizales: 1. This research was
sponsored by; Company/Drug; Merck & Co., Inc./Ridaforolimus. R.
Lush: 1. This research was sponsored by; Company/Drug; Merck &
Co., Inc./Ridaforolimus. K. Papadopoulos: 1. This research was sponsored
by; Company/Drug; Merck & Co., Inc./ Ridaforolimus.
BACKGROUND: RIDA, a unique rapamycin analog and potent
inhibitor of mTor signaling, is being developed for the treatment of solid
tumors. In vitro data indicate RIDA is a reversible and time- dependent
inhibitor of CYP3A. Based on a theoretical equation for modeling
time-dependent inhibition, an increase in plasma AUC between 1.13-
and 1.25-fold was projected for a CYP3A substrate (MDZ) in the presence
of therapeutic concentrations of RIDA. The study aim was to
assess the effect of MD RIDA on the SD PK of MDZ.
METHODS: This was a 2 part study; Part 1 was an open-label, fixedsequence
design. Sixteen patients with advanced cancer received an oral
SD of 2 mg MDZ on Day -2 (baseline). On Days 1-5 patients received
once daily RIDA 40 mg (5 consecutive days); on Day 5 a SD of 2 mg
MDZ was administered simultaneously with RIDA. Part 1 was complete
at the end of Day 5 procedures. Plasma was collected for MDZ assay.
Part 2 was an extension phase until disease progression; PK data were
not collected.
RESULTS: Fifteen patients were evaluated for PK. The geometric
mean ratios (GMR) (90% CI) of MDZ + RIDA versus MDZ for AUC 0-∞
and C max were 1.23 (1.07, 1.40) and 0.92 (0.82, 1.03), respectively.
T max and apparent t 1/2 were similar (Table). The observed 1.23fold
increase in MDZ AUC 0-∞ in the presence of RIDA was consistent
with model predictions.
Midazolam Alone
Parameter
AUC0-10 (nghr/ml) †
C0-10 (ng/ml) †
T0-10 (hr) ‡
Apparent10 (hr) ı
N
95% CI N
95% CI GMR 90% CI rMSE
15
(36.03, 58.69) 15
(44.19, 71.98) 1.23 (1.07, 1.40)
15
(15.12, 20.11) 15
(13.91, 18.50) 0.92 (0.82, 1.03)
15
(0.3, 1.0) 15
(0.3, 1.5)
15
2.4 15
3.3
ı
Ridaforolimous + Midazolam (Ridaforolimous
+ Midazolam /
Midazolam Alone)
GM
GM
45.99
56.40
0.208
17.44
16.04
0.177
0.5
0.5
-
4.9
5.3
-
ı rMSE: Square root of conditional mean squared error (residual error) from the linear mixed effect model rMSE*100%
approximates the within-subject %CV on the raw scale
† Back-tranformed least-squares mean and confidence interval from linear mixed effects model performed on natural
log-transformed values; GMR = Geometric least-squares mean ratio ([Ridaforolimus + Midazolam]/Midazolam alone)
‡ Median (min, max) reported for Tmax
ı Harmonic mean, jack-knife standard deviation reported for apparent t1-2
GM Geometric Least-Squares Mean; CI: Confidence Interval
s22 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
CONCLUSION: Multiple doses of 40 mg RIDA for 5 days results
in no clinically meaningful alterations of CYP3A activity and therefore
RIDA can be administered with sensitive CYP3A substrates.
PI-40
THE BIOAVAILABILITY OF AN ORAL LIQUID FORMULA-
TION (OLF) RELATIVE TO A FORMULATED CAPSULE (FC)
OF CRIZOTINIB, A DUAL ALK/MET INHIBITOR, IN HEALTHY
SUBJECTS. H. Xu, 1 M. O’Gorman, 1 W. Tan, 2 C. Leister, 3 M. Monajati,
2 N. Brega, 4 G. Ni, 1 S. Phillips, 1 L. Mendes da Costa, 5 A. Bello 6 ;
1 Pfizer Inc, Groton, CT, 2 Pfizer Inc, La Jolla, CA, 3 Pfizer Inc, Collegeville,
PA, 4 Pfizer Inc, Milan, Italy, 5 Pfizer Inc, Brussels, Belgium,
6 Pfizer Inc, New York, NY. H. Xu: 1. This research was sponsored
by; Company/Drug; Pfizer. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer. M. O’Gorman: 1. This research was sponsored
by; Company/Drug; Pfizer. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer. W. Tan: 1. This research was sponsored
by; Company/Drug; Pfizer. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer. C. Leister: 1. This research was sponsored
by; Company/Drug; Pfizer. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer. M. Monajati: 1. This research was sponsored
by; Company/Drug; Pfizer. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer. N. Brega: 1. This research was sponsored by;
Company/Drug; Pfizer. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer. G. Ni: 1. This research was sponsored by; Company/Drug;
Pfizer. 2. I am a paid consultant/employee for; Company/
Drug; Pfizer. S. Phillips: 1. This research was sponsored by; Company/Drug;
Pfizer. 2. I am a paid consultant/employee for; Company/
Drug; Pfizer. L. Mendes da Costa: None. A. Bello: 1. This research
was sponsored by; Company/Drug; Pfizer. 2. I am a paid consultant/
employee for; Company/Drug; Pfizer.
BACKGROUND: Crizotinib (CRZ) is an orally administered
selective small molecule ATP-competitive inhibitor of the anaplastic
lymphoma kinase (ALK) and MET/HGF receptor tyrosine kinases
and has recently been approved, as Xalkori, for the treatment of
ALK-positive non-small cell lung cancer (NSCLC). An oral liquid
formulation (OLF) is under development in order to provide dosing
options for patients unable to swallow the marketed formulated
capsule (FC).
METHODS: Two single oral CRZ doses given as OLF and FC,
separated by at least 14 days were administered to 22 healthy subjects
under fasted condition in an open-label, randomized, 2-period, 2-treatment,
2-sequence, cross-over study. Plasma concentrations of CRZ and
its metabolite PF-06260182, from serial samples collected after each
dose, were determined using a validated HPLC-MS/MS method. Pharmacokinetic
(PK) parameters for CRZ and PF-06260182 were derived
from plasma concentration-time data using non-compartmental methods.
The relative bioavailability of CRZ when given as the OLF and FC
was determined as the ratio (OLF/FC) of the adjusted geometric means
of CRZ AUC inf . Bioequivalence was to be concluded if the 90% confidence
intervals (CIs) for ratios of CRZ AUC inf and C max were within
80 - 125%.
RESULTS: The CRZ plasma concentration time profiles with
the OLF and FC were super imposable and a median T max value of
5.0 hours was determined for both formulations. The ratios of adjusted
geometric means (90% confidence interval) of CRZ AUC inf and C max
were 99.58% (91.08%, 108.87%) and 96.84% (88.22%, 106.32%),
respectively. PK parameters of CRZ were similar following the administration
of the two formulations. The plasma concentration time profiles
and estimated pharmacokinetic parameters for PF-06260182 were
also similar for the two formulations.
CONCLUSION: The bioavailability of crizotinib given as the OLF
relative to the FC was 99.6% and the two formulations were determined
to be bioequivalent.
aBsTraCTs
PI-41
ASSOCIATION OF ABCC2 POLYMORPHISMS WITH CISPL-
ATIN DISPOSITION AND EFFICACY. J. A. Sprowl, 1 V. Gregorc, 2
C. Lazzari, 2 R. H. Mathijssen, 3 W. J. Loos, 3 A. Sparreboom 1 ; 1 St Jude
Children’s Research Hospital, Memphis, TN, 2 Scientific Institute
University Hospital San Raffaele, Milan, Italy, 3 Erasmus MC, Rotterdam,
Netherlands. J.A. Sprowl: None. V. Gregorc: None. C. Lazzari:
None. R.H. Mathijssen: None. W.J. Loos: None. A. Sparreboom:
None.
BACKGROUND: ABCC2 (MRP2) is a polymorphic ATP-binding
cassette transporter that is important in detoxification by transporting
compounds such as the anticancer agent cisplatin. ABCC2 is highly
expressed in certain cisplatin-resistant tumors and on the apical membrane
of renal proximal tubular cells. We hypothesized that ABCC2
may be involved in the luminal secretion of cisplatin, thereby affecting
drug disposition and pharmacodynamic profiles.
METHODS: Experimental studies were performed in Abcc2deficient
mice and in the NCI60 cancer cell line panel. Two cohorts of
adult Caucasians with advanced non-small cell lung cancer (NSCLC)
were treated with cisplatin-based chemotherapy (dose, 50-100 mg/
m 2 ). Each patient’s DNA was screened for single-nucleotide polymorphisms
(SNPs) in ABCC2 by direct nucleotide sequencing.
RESULTS: In clinical samples, 7 SNPs in ABCC2 and 18 different
haplotypes were identified. In cohort 1 (n=112), individual SNPs
were not significantly associated with systemic clearance of unbound
cisplatin (P>0.12), with renal clearance of cisplatin (P>0.05), or with
the percentage change in serum creatinine from baseline, a marker
of nephrotoxicity. In cohort 2 (n=125), response rate (P>0.41), progression-free
survival (P>0.63), and overall survival (P>0.81) were
also not associated with the studied SNPs. In Abcc2-deficient mice,
the cumulative urinary excretion of cisplatin was unchanged compared
with wild type mice (85.5±13.9 vs 85.5±8.37%), as were serum
creatinine levels (P>0.05). These findings are consistent with a lack
of correlation between (i) SNPs and mRNA expression in cancer cells
(P>0.26), and (ii) mRNA expression and cisplatin-induced cytotoxicity
(R=-0.05; P=0.21).
CONCLUSION: Our study suggests that common ABCC2 variants
do not substantially contribute to explaining the extensive interindividual
variability in cisplatin disposition and efficacy.
PI-42
CONTRIBUTION OF P53 SIGNALING TO CISPLATIN NEPH-
ROTOXICITY IN OCT1/2-DEFICIENT MICE. C. S. Lancaster, J. A.
Sprowl, R. M. Franke, A. A. Gibson, L. Li, D. Finkelstein, L. Janke,
A. Sparreboom; St Jude Children’s Research Hospital, Memphis, TN.
C.S. Lancaster: None. J.A. Sprowl: None. R.M. Franke: None.
A.A. Gibson: None. L. Li: None. D. Finkelstein: None. L. Janke:
None. A. Sparreboom: None.
BACKGROUND: We previously reported that tubular secretion of
cisplatin is abolished in Oct1/Oct2-deficient [Oct1/2(-/-)] mice, and
that these animals are protected from severe cisplatin-induced kidney
damage (Franke et.al. CCR 2010). Since tubular necrosis was not completely
absent in Oct1/2(-/-) mice, we hypothesized that other pathways
are involved in the observed injury.
METHODS: Studies were done in female wild type, Oct1/2(-/-), or
p53(+/-) animals receiving i.p. cisplatin at 10-15 mg/kg. The cisplatinglutathione
metabolites GSH1 and GSH2 were analyzed using LC/
MS/MS, and gene expression was assessed using Affymetrix microarrays
and RT-PCR arrays.
RESULTS: Expression levels of putative cisplatin transporters
(eg, Abcc2, Slc31a1) or the glutathione transporter Slc22a8 were not
altered in kidneys of Oct1/2(-/-) mice. In line with this finding, urinary
levels of GSH1/GSH2 to total platinum were unchanged compared to
wild type mice (P>0.15). In addition, γ-glutamyltranspeptidase (GGT)
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s23

aBsTraCTs nature publishing group
and expression of the GGT-pathway genes Ggt1, Anpep and Ccbl1
was unaffected. KEGG pathway analyses on kidneys from treated
mice revealed that the most significantly altered genes were associated
with the p53 signaling network, including Cdnk1a and Mdm2, both in
wild type mice (P=2.40×10 -11 ) and Oct1/2(-/-) mice (P=1.92×10 -8 ).
The significance of this pathway was confirmed in subsequent experiments
demonstrating that even heterozygosity for a p53-null allele
already resulted in amelioration of cisplatin nephrotoxicity. Furthermore,
administration of pifithrin-α, an inhibitor of p53-dependent transcriptional
activation, decreased cisplatin-induced kidney damage in
Oct1/2(-/-) mice compared to vehicle control.
CONCLUSION: These findings indicate that (i) the p53 pathway
plays a crucial role in response to cisplatin treatment and (ii) clinical
exploration of OCT2 inhibitors may not lead to complete nephroprotection
unless this pathway is simultaneously attacked.
PI-43
CONTRIBUTION OF METABOLISM TO SORAFENIB PHAR-
MACOKINETIC VARIABILITY. E. I. Zimmerman, J. L. Roberts,
L. Li, A. Gibson, J. E. Rubnitz, H. Inaba, S. D. Baker; St. Jude Children’s
Research Hospital, Memphis, TN. E.I. Zimmerman: None.
J.L. Roberts: None. L. Li: None. A. Gibson: None. J.E. Rubnitz:
None. H. Inaba: 6. I will be discussing the following product, which
is not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Bayer Pharmaceuticals/sorafenib, Onyx
Pharmaceuticals/sorafenib. S.D. Baker: None.
BACKGROUND: Sorafenib is a multikinase inhibitor currently
under clinical investigation for the treatment of acute myeloid
leukemia (AML). The purpose of our study was to characterize sorafenib
metabolism in pediatric AML patients and determine the UDPglucuronosyltransferase
(UGT) and cytochrome P450 (CYP) enzymes
involved in sorafenib metabolism.
METHODS: Sorafenib was administered (150 or 200 mg/m 2 twice
daily) and PK sampling was performed at steady-state. Sorafenib
metabolism was assessed in vitro using human liver microsomes and
recombinant UGT and CYP isozymes. The effect of azole antifungals
on sorafenib metabolism by UGT1A9 and CYP3A4 was determined
in vitro. Sorafenib and metabolites were measured in human plasma
and in vitro metabolic reaction mixtures by LC-MS/MS.
RESULTS: In 22 children with AML (14 males; median age, 9 yr
[range, 1-17 yr]), the median (range) conversion rate of sorafenib to
sorafenib N-oxide, an active metabolite, was 20% (5.2%-69%). Notably,
metabolism to N-oxide was highest (> 30%) in males aged 5-10 yr.
Sorafenib was predominantly metabolized by UGT1A9 to sorafenib
glucuronide (Km = 3.6 μM) and by CYP3A4 to the N-oxide (Km =
12 μM, Vmax = 3.1 nmol/min/nmol). Ketoconazole inhibited sorafenib
metabolism by UGT1A9 (Ki = 2.2 μM), while ketoconazole, posaconazole
and voriconazole inhibited CYP3A4-mediated metabolism
(Ki = 0.17, 0.38, and 39 μM, respectively). Patients receiving concurrent
voriconazole or posaconazole had the lowest sorafenib N-oxide
conversion rates to the N-oxide (

nature publishing group
laboratory data were entered into a stepwise regression for the first half
of patients’ enrolled (derivation (D) cohort). The regression model was
then evaluated in the remainder of the patients (validation (V) cohort).
RESULTS: A total of 768 patients were included in the analysis, the
first 418 in the derivation and remaining 350 in the validation cohort.
Only BL glu in ATEN and BL glu and BL insulin (ins) in HCTZ
retained significance in the validation cohort (Table). The correlation
between the model-predicted versus observed glu change in the validation
cohort was r=0.4343 for ATEN and r=0.3168 for HCTZ.
CONCLUSION: Baseline glucose is the main predictor of drugassociated
rise in glucose during treatment with both ATEN and
HCTZ. No other clinical variables were validated as predictors with
ATEN; and only BL insulin was an additional predictor for HCTZ.
However, overall, these clinical factors have low predictive value for
drug-associated glucose rise.
ATEN HCTZ
Partial Model Parameter Partial Model Parameter
R2 R2 Estimate P-value R2 R2 Estimate P-value
D BL glu 0.1159 0.1159 -0.2995

aBsTraCTs nature publishing group
RESULTS: The distribution kinetics of GlySar at the blood-CSF
barrier are best described by a three-compartment model with the predicted
GlySar concentrations highly correlated to the observed values
in blood and CSF. The estimated blood clearance values are 0.233 and
0.447 mL/min in wild-type and PEPT2 knockout mice, respectively.
Total efflux CL from CSF to blood was 5-fold higher for wild-type
mice compared to PEPT2 knockout mice and it demonstrates that
PEPT2 plays an important role in the elimination and CSF distribution
of GlySar, and serves as an efflux pump at the blood-CSF barrier.
Based on estimated parameter values, it seems that the active efflux CL
by PEPT2 contributes to 80% of total efflux CL in brain of wild-type
mice and the rest of 20% is mediated by bulk and diffusion CL.
CONCLUSION: In vivo CNS distribution kinetics of PEPT2 substrates
depending on PEPT2 expression level can be well described by
a three-compartment model using NONMEM approach. Given individual
PEPT2 expression level, it may be possible to elucidate and predict
the transfer kinetics of PEPT2 substrates in human CSF and brain
using this modeling approach.
PI-50
NO EFFECTS OF GENDER, AGE AND FOOD ON THE PHAR-
MACOKINETICS OF CC-930 IN HEALTHY SUBJECTS. M. E.
Thomas, Jr, A. Wu, L. Liu, L. Kong, S. Choudhury, Y. Yes, M. Parmesan,
O. L. Laski; Colene Corporation, Summit, NJ. M.E. Thomas, Jr:
None. A. Wu: None. L. Liu: None. L. Kong: None. S. Choudhury:
None. Y. Ye: None. M. Parmesan: None. O.L. Laski: None.
BACKGROUND: To assess the effects of gender, age and food on
the pharmacokinetics (PK) of CC-930 in healthy subjects (HS).
METHODS: 36 HS were enrolled and distributed equally into
3 groups. Groups 1 & 2 consisted of young females & males, respectively,
ages 18-55 (inclusive). Group 3 consisted of elderly HS, ages
65-85 (inclusive). All HS received a single 100 mg dose of CC-930
under fasting conditions and Group 2 HS received a second single
100 mg dose of CC-930 under fed conditions in a randomized,
2- period, crossover fashion. Serial blood samples were collected for
determination of plasma CC-930 concentrations.
RESULTS: 7 HS (19.44%) reported a total of 8 treatment-emergent
adverse events (TEAEs). TEAEs included Malia, pain in extremity, ear
disorder, excoriation, headache, rhino rhea & mental status change.
No TEAEs were deemed related to CC-930. Primary PK parameters
are summarized below. Mean AUCs of CC-930 were similar between
females & males, with mean C max slightly decreased in females. Mean
AUCs of CC-930 were similar between elderly & young HS, with
mean C max slightly increased in the elderly. Mean AUCs of CC-930
were similar when HS were dosed either with or without food, with
mean C max slightly lower with food. Median T max was not affected by
gender or age; however, food delayed T max by ~3 hours.
CONCLUSION: There were no clinically relevant effects of gender,
age or food on the PK of CC-930. CC-930 was well-tolerated in
all subjects when a single 100 mg dose was administered under fasting
and/or fed conditions.
Geometric Mean (Geometric CV%)
Gender Effect
(Groups 1-3)
FEMALES
(N = 17)
C max (ng/mL) 586.80
(58.0)
AUC 0-t
(ng*hr/mL)
AUC 0-inf
(ng*hr/mL)
13050.01
(26.9)
13663.99
(28.9)
T max (hr)* 2.00
(1.00-8.00)
MALES
(N = 19)
645.79
(38.0)
14034.74
(25.5)
14983.12
(26.7)
1.50
(1.00-4.00)
Age Effect
(Groups 1-3)
YOUNG
(N = 24)
602.02
(39.1)
13501.88
(25.5)
14398.28
(27.6)
1.52
(1.00-8.00)
*Median (minimum - maximum); N = Number of subjects
ELDERLY
(N = 12)
648.81
(64.6)
13679.40
(28.3)
14239.14
(29.4)
1.50
(1.00-4.00)
FASTING
(N = 12)
658.46
(31.3)
14376.45
(24.8)
15584.10
(25.4)
Food Effect
(Group 2)
1.00
(1.00-2.50)
FED
(N = 12)
571.69
(20.1)
14744.60
(22.7)
16177.79
(23.1)
4.00
(2.00-8.00)
PI-51
SAFETY/TOLERABILITY AND PHARMACOKINETICS OF
MULTIPLE ORAL DOSES OF APREMILAST IN HEALTHY MALE
SUBJECTS. A. Wu, 1 P. Rohane, 1 J. Ng, 2 B. DeGroot, 2 B. Colgan, 2 O.
L. Laskin 1 ; 1 Celgene Corp., Summit, NJ, 2 Celerion, Inc., Lincoln, NE.
A. Wu: 1. This research was sponsored by; Company/Drug; Colene
Corp. 2. I am a paid consultant/employee for; Company/Drug; Colene
Corp. P. Roane: 1. This research was sponsored by; Company/Drug;
Celgene Corp. J. Ng: None. B. DeGroot: None. B. Colgan: None.
O.L. Laskin: 1. This research was sponsored by; Company/Drug;
Celgene Corp.
BACKGROUND: To evaluate the safety/tolerability and pharmacokinetics
(PK) of ascending multiple oral doses of apremilast (APR)
in healthy subjects (HS).
METHODS: Staggered parallel, double-blind, randomized, placebo-controlled
trial where cohorts received ascending dose regimes of
APR 40, 60, or 80 mg QD; 40 mg BID; 40 mg QD with dose titration
(10 , 20, and 40 mg on Days 1-3, 4-6, and 7-14, respectively), or a
matching placebo for 14 days. A total of 55 HS were equally allocated
to one of the 5 cohorts (each cohort randomized to 9 active, 2 placebo).
RESULTS: APR was absorbed rapidly with t max of 2-3 hours, and
was eliminated in a biphasic manner with terminal elimination t 1/2
ranging from 6-9 hours. The PK profiles on Days 1 and 14 were similar
with minimum accumulation. Following single dose and at steady
state, systemic exposure (C max and AUC) appeared to increase in a less
than dose proportional manner with 40% inter-subject variability. Less
than 4% of APR was excreted in urine as parent drug. One or more
treatment emergent adverse events (TEAE) were seen in 42 (93%)
HS receiving APR compared to 5 (50%) HS receiving placebo. The
most frequently reported AEs with apremilast compared to placebo
were nausea 71% vs 10%, headache 60% vs. 10%, upper abdominal
pain 22% vs. 0%, dizziness 20% vs. 10%, diarrhea 18% vs. 0% and
vomiting 13% vs. 0%, respectively. At 40 mg daily dose, nausea was
reported by 44% HS with, and 78% HS without dose titration. Vomiting
was observed in 1HS at 40 mg BID compared to 4 HS at 80 mg
QD. Microscopic hematuria was only seen in 2 HS at 80 mg QD dose.
The majority of TEAEs were mild in severity, resolved without treatment,
and were suspected to be related to APR.
CONCLUSION: APR was tolerated in HS at doses up to 80 mg
daily (40 mg BID) for 14 days. APR systemic exposure increased in a
sub-dose proportional manner with moderate variability. APR is subject
to nonrenal clearance mechanisms.
PI-52
POPULATION PHARMACOKINETIC ANALYSIS OF (R)- AND
(S)-KETAMINE AND NORKETAMINE IN RATS ON AD LIB AND
CALORIE RESTRICTED DIETS. A. Ramamoorthy, 1 S. Van Wart, 2
R. de Cabo, 1 D. Mager, 2 I. Wainer 1 ; 1 National Institute on Aging
(NIA/NIH), Baltimore, MD, 2 University at Buffalo, Buffalo, NY.
A. Ramamoorthy: None. S. Van Wart: None. R. de Cabo: None.
D. Mager: None. I. Wainer: None.
BACKGROUND: Diet and nutritional status can affect drug
metabolism. Caloric restriction (CR) can increase the activity of the
cytochrome P450 (CYP) enzymes, alter the regioselectivity of CYPs,
and enhance drug metabolism. Ketamine (KET) is effectively used in
the treatment of pain and depression. The purpose of this study was
to assess the impact of CR on the pharmacokinetics (PK) of both the
(R)- and (S)-ketamine (KET) enantiomers and its key metabolite norketamine
(NKET).
METHODS: Male Fisher rats fed on an ad libitum diet (n=30;
avg wt 426 g) and a CR diet (n=30; avg wt 240 g) were given a single
90 mg/kg dose of racemic KET hydrochloride intraperitoneally
(IP). The (S)- and (R)-KET and (S)- and (R)-NKET plasma concentrations
were determined by HPLC. Separate population PK models
were developed for the (R)- and (S)-KET and (R)- and (S)-NKET in
NONMEM using a naïve pooled approach. CR was tested as a covariate
on each model parameter using a likelihood ratio test (α=0.001).
s26 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
RESULTS: A one-compartment model was able to characterize
the KET and NKET concentration-time profiles for both the (R) and
(S) analyses. CR resulted in a statistically significant increase in the
relative IP bioavailability for both (R)-KET (2.05-fold) and (S)-KET
(1.88-fold). The increase in relative bioavailability is greater than what
would be expected based upon differences in body weight, suggesting
additional mechanisms for altered KET PK. CR also resulted in a statistically
significant increase in the formation rate of (R)-NKET (1.2fold)
and a decrease in the elimination rate of (R)-NKET (2.15-fold).
CONCLUSION: CR alters the PK of (R)- and (S)-KET and selectively
increases the net exposure to (R)-NKET in rats. Diet and nutritional
status may therefore need to be considered when administering
KET.
PI-53
DETERMINATION OF KETAMINE AND ITS DOWN-
STREAM METABOLITES IN PLASMA AND BRAIN OF WIS-
TAR RATS. M. Sanghvi, 1 R. Moaddel, 1 K. OLoughlin, 2 C. Green, 2
A. Ramamoorthy, 1 I. Wainer 1 ; 1 NIA/NIH, Baltimore, MD, 2 SRI International,
Menlo Park, CA. M. Songhai: None. R. Moaddel: None.
K. Laughlin: None. C. Green: None. A. Ramamoorthy: None.
I. Wainer: None.
BACKGROUND: (R,S)-Ketamine (K) is effective in the treatment
of depression and chronic pain. K is extensively metabolized to norketamine
(NK), dehydronorketamine (DHNK), hydroxynorketamines
(HNK) and hydroxyketamines (HK). We evaluated the distribution of
K and its downstream metabolites in the brain and plasma of Westar
rats.
METHODS: Male Westar rats were dual catheterized and (R,S)-
Kept (40 mg/kg) was administered through one and plasma samples
were collected from the other at 5, 10, 20, 40 and 60 min, 2h, 4h, 8h,
12h, 24h and 72h and brains were collected at 10, 30 and 60 min and
4h (n = 3). Plasma and brain concentrations of K at its downstream
metabolites were determined using a LC-MS/MS assay, blood partitioning
studies were also carried out for all analyses.
RESULTS: K, NK and DHNK, (2S,6S;2R,6R) HNK (4a),
(2S,6R;2R,6S) HNK (4b), (2S,5S;2R,5R) HNK and (2S,5R;2R,5S)
HNK were measured in plasma, with 4a being a major metabolite,
maximum concentration 2621 ng/ml at 40 min. The metabolites
were also measured in the CNS, with 4a reaching maximum concentrations
of 1571 ng/ml at 30 min and 4b reaching 769 ng/ml at
10 min. The transport of NK into the CNS was enantioselective with
R-NK concentrations 5 times higher than S-NK at 10 min. Low levels
of DHNK were also detected in plasma and brain, and blood partition
studies indicate that 80% of DHNK was partitioned into red
blood cells.
CONCLUSION: The results demonstrate that while NK is the
initial metabolite, it is not the major metabolite and that downstream
metabolites enter the CNS. The data suggest that future clinical studies
of K should include the analysis of all of its metabolites as they may
play a key role in the therapeutic properties of K.
PI-54
POPULATION PHARMACODYNAMICS OF NADROPARIN
IN MORBIDLY OBESE PATIENTS USING ANTI-XA LEVELS AS
PHARMACODYNAMIC ENDPOINT. J. Diepstraten, E. J. Janssen,
C. M. Hacking, S. van Kralingen, M. Y. Peeters, E. P. van Dongen,
R. J. Wiezer, B. van Ramshorst, C. A. Knibbe; St. Antonius Hospital,
Nieuwegein, Netherlands. J. Diepstraten: None. E.J. Janssen: None.
C.M. Hackeng: None. S. van Kralingen: None. M.Y. Peeters: None.
E.P. van Dongen: None. R.J. Wiezer: None. B. van Ramshorst:
None. C.A. Knibbe: None.
BACKGROUND: Morbidly obese patients (body mass index
(BMI) > 40 kg/m2) are at increased risk for thromboembolism, especially
after surgery. In clinical practice a double dose of nadroparin
for thrombosis prophylaxis is often used in (morbidly) obese patients,
aBsTraCTs
without proper pharmacodynamic studies. The aim of this study was
to develop a population pharmacodynamic (PD) model of nadroparin
administered for thrombotic prophylaxis in morbidly obese patients,
using anti Xa-levels as a PD endpoint.
METHODS: In a prospective study in morbidly obese patients
undergoing bariatric surgery, 5700 IU nadroparin was administered
subcutaneously at induction of anesthesia. Until 24 hours after administration,
11 samples per patient were collected for chromogenic
anti-Xa level measurement. Population PD modeling was developed
using NONMEM VI. A step-wise covariate analysis was performed
using total body weight (TBW), lean body weight (LBW), ideal body
weight, BMI, age, sex, creatinine and bilirubin.
RESULTS: Data of 20 morbidly obese patients with a median total
body weight of 144 kg (range 112 - 260 kg) and a median lean body
weight of 66 kg (range 54 - 100 kg) were best described by a twocompartment
pharmacodynamic disposition model. Lean body weight
was the most predictive covariate for volume of distribution (Vss = 12.6
L * (LBW/66) 1.5 ) while total body weight proved to be the most predictive
covariate for clearance (CL = 47.6 mL/min *(TBW/144) 1.5 . The
delay in pharmacodynamic effect of nadroparin was adequately characterized
using a transit compartment with a mean transit rate constant of
0.006 min -1 and a mean absorption rate constant of 0.022 min -1 ).
CONCLUSION: A population pharmacodynamic model for
nadroparin in morbidly obese patients was developed using anti-Xa
levels as endpoint. As lean bodyweight proved the most predictive
covariate for volume of distribution, further study on dose adjustment
based on lean body weight in morbidly obese patients should be considered.
PI-55
DEVELOPMENTAL PHARMACOKINETICS OF PROPYLENE
GLYCOL IN PRETERM AND TERM NEONATES. R. F. De Cock, 1
K. Allegaert, 2 A. Kulo, 3 J. de Hoon, 2 R. Verbesselt, 2 M. Danhof, 1
C. A. Knibbe 4 ; 1 Leiden University (LACDR), Leiden, Netherlands,
2 University Hospital Leuven, Leuven, Belgium, 3 University of Sarajevo,
Sarajevo, Bosnia Herzegovina and University Hospital Leuven,
Leuven, Belgium, 4 Leiden University (LACDR), Leiden, Netherlands
and St. Antonius Hospital, Nieuwegein, Netherlands. R.F. De Cock:
None. K. Allegaert: None. A. Kulo: None. J. de Hoon: None.
R. Verbesselt: None. M. Danhof: None. C.A. Knibbe: None.
BACKGROUND: Propylene glycol (PG) is often used as a cosolvent
in drug formulations such as phenobarbital and lorazepam. As
these formulations may also be used in neonates, the aim of this study
was to characterize the pharmacokinetics of propylene glycol when
co-administered intravenously with paracetamol (0.8 mg PG/mg paracetamol)
or phenobarbital (3.5 mg PG/mg phenobarbital) in (pre)term
neonates.
METHODS: A population pharmacokinetic analysis was performed
based on 372 PG plasma concentrations following PG co-administration
with paracetamol or phenobarbital in 62 (pre)tem neonates (birth
weight 630-3980 g, postnatal age 1-30 days) using NONMEM 6.2.
The final model was used to simulate propylene glycol exposure upon
administration of PG with different drug formulations in neonates
(gestational age 24-40 weeks).
RESULTS: In the one compartment model, birth weight (BWb)
and postnatal age (PNA) were both identified as covariates for clearance
using an allometric function (CL i = 0.0849 x {((BWb/2720) 1.69 )
x ((PNA/3) 0.201 )}). Volume of distribution scaled allometricly with
current bodyweight (V i = 0.967 x {((BW/2720) 1.45 )}), and was 1.77
times higher in neonates receiving phenobarbital instead of paracetamol.
The final model shows that PG trough concentrations at steady
state are expected to range between 19.8-109.3 and 6.4-56.1 mg/L for
paracetamol and phenobarbital formulations, respectively, depending
on weight and age of the neonates. Even higher concentrations are
expected when PG is co-administered with lopinavir/ritonavir (152.7
mg PG/mL lopinavir/ritonavir solution) or lorazepam (414 mg PG/mg
lorazepam) in currently used dosages.
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s27

aBsTraCTs nature publishing group
CONCLUSION: A pharmacokinetic model was developed for
propylene glycol co-administered with paracetamol or phenobarbital
in (pre)term neonates. This model may be used to simulate propylene
glycol concentrations upon PG administration with paracetamol or
phenobarbital, and potentially other drugs in neonates.
PI-56
EXTRAPOLATION OF THE DEVELOPMENTAL GLOMERU-
LAR FILTRATION RATE MODEL DERIVED FROM AMIKACIN
CLEARANCE TO NETILMICIN AND VANCOMYCIN IN PRE-
TERM AND TERM NEONATES. R. F. De Cock, 1 K. Allegaert, 2
C. M. Sherwin, 3 M. de Hoog, 4 J. N. van den Anker, 5 M. Danhof, 1
C. A. Knibbe 6 ; 1 Leiden University (LACDR), Leiden, Netherlands,
2 University Hospital Leuven, Leuven, Belgium, 3 University of Utah
School of Medicine, Salt Lake City, UT, 4 Erasmus MC - Sophia Children’s
Hospital, Rotterdam, Netherlands, 5 Erasmus MC - Sophia
Children’s Hospital, Rotterdam, Netherlands and Children’s National
Medical Center, Washington, WA, 6 Leiden University (LACDR), Leiden,
Netherlands and St. Antonius Hospital, Nieuwegein, Netherlands.
R.F. De Cock: None. K. Allegaert: None. C.M. Sherwin: None.
M. de Hoog: None. J.N. van den Anker: None. M. Danhof: None.
C.A. Knibbe: None.
BACKGROUND: The aim of this study was to evaluate whether
the developmental glomerular filtration rate (GFR) model derived from
amikacin clearance [1] can be used to describe maturation in clearance
of other renally excreted antibiotics such as netilmicin and vancomycin
in (pre)term neonates.
METHODS: For netilmicin and vancomycin, 386 and 752 concentrations
were available from 97 (BWb 470-3000g, PNA 1-30 days)
and 273 (BWb 385-2550g, PNA 1-30 days) neonates, respectively. A
pharmacokinetic model was developed for both drugs using the developmental
GFR model [1] and on the basis of a comprehensive covariate
model. The descriptive and predictive performance of models developed
using the two approaches were compared.
RESULTS: For netilmicin and vancomycin, the developmental GFR
model derived from amikacin clearance resulted in adequate goodness of
fit plots (figure). Visual inspection showed no differences with goodness
of fit plots obtained with the comprehensive covariate models, although
the objective function was 5 (p

nature publishing group
discussion, or the product is still investigational; Company/Drug;
MLTA3698A. B. Emu: 1. This research was sponsored by; Company/
Drug; Genentech Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; MLTA3698A. M. Tang: 1. This
research was sponsored by; Company/Drug; Genentech Inc. 6. I will
be discussing the following product, which is not labeled for the use
under discussion, or the product is still investigational; Company/
Drug; MLTA3698A. J.F. Visich: 1. This research was sponsored by;
Company/Drug; Genentech Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; MLTA3698A.
BACKGROUND: MLTA3698A is a humanized monoclonal antibody
against lymphotoxin-α (LTα), a transiently expressed cytokine
on activated B and T cells implicated in rheumatoid arthritis (RA)
pathogenesis. In this study, pharmacokinetics (PK) and pharmacodynamics
(PD) of MLTA3698A were characterized in RA patients.
METHODS: This Phase I, randomized, double blinded, placebocontrolled
study consisted of a single ascending dose phase at 0.3-5
mg/kg IV, 1 or 3 mg/kg SC (n=30) and a multiple ascending dose
phase at 1 or 3 mg/kg SC or 5 mg/kg IV every 2 weeks for 3 doses
(n=35). Serum samples were analyzed for MLTA3698A, soluble LTα
(sLTα), CXCL13 and anti-therapeutic antibodies (ATAs). A population
PK-PD model was developed to characterize the PK properties
of MLTA3698A, and relationships between PK and PD outcomes of
sLTα and CXCL13.
RESULTS: MLTA3698A PK data were adequately described by a
2-compartment model with first-order SC absorption. The estimated
clearance and central distribution volume were 454 mL/day and 3.96
L, respectively, and the SC bioavailability was 42.7%. Preliminary
covariate analysis indicated that body weight was not a significant covariate
of PK, supporting flat dosing. ATAs were detected post-dose in
7 of 52 patients treated with MLTA3698A with no consistent effect on
PK. Dose dependent increases in total sLTα were observed, consistent
with the increased half-life of sLTa upon binding to drug, as confirmed
by PKPD modeling. Decreases in CXCL13, a chemokine associated
with RA disease activity and induced downstream of LTbR signaling,
were observed at MLTA3698A doses ≥ 1 mg/kg. PK-PD modeling
using an indirect response model estimated ~50% maximum CXCL13
suppression and an IC50 of ~0.9 μg/mL.
CONCLUSION: MLTA3698A exhibited linear PK with 42.7%
SC bioavailability. MLTA3698A demonstrated target binding as evidenced
by the accumulation of total sLTα and pharmacological activity
as indicated by the suppression of the PD biomarker CXCL13.
PI-59
THE SINGLE DOSE PHARMACOKINETIC (PK) AND PHAR-
MACODYNAMIC (PD) PROFILES OF SUVOREXANT (MK-4305),
A DUAL OREXIN RECEPTOR ANTAGONIST, IN HEALTHY
MALE SUBJECTS. H. Sun, 1 D. Kennedy, 2 N. Lewis, 1 T. Laethem, 3
K. Yee, 4 X. Li, 1 J. Hoon, 5 L. Van Bortel, 6 L. Rosen, 1 J. Chodakewitz, 1
J. Wagner, 7 G. Murphy 1 ; 1 Merck, North Wales, PA, 2 Genentech, South
San Francisco, CA, 3 Merck, Brussels, Belgium, 4 Merck, West Point,
PA, 5 U.Z. Gasthuisberg, Center for Clinical Pharmacology, Leuven,
Belgium, 6 U.Z. Gent, Drug Research Unit Gent, Gent, Belgium,
7 Merck, Rahway, NJ. H. Sun: 1. This research was sponsored by;
Company/Drug; Merck. 2. I am a paid consultant/employee for;
Company/Drug; Merck. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is still
investigational; Company/Drug; suvorexant. D. Kennedy: 2. I am a
paid consultant/employee for; Company/Drug; Genentech. N. Lewis:
2. I am a paid consultant/employee for; Company/Drug; Merck.
T. Laethem: 2. I am a paid consultant/employee for; Company/Drug;
Merck. K. Yee: 2. I am a paid consultant/employee for; Company/
Drug; Merck. X. Li: 2. I am a paid consultant/employee for; Company/Drug;
Merck. J. Hoon: 2. I am a paid consultant/employee
for; Company/Drug; Merck. L. Van Bortel: 2. I am a paid consultant/employee
for; Company/Drug; Merck. L. Rosen: 2. I am a paid
aBsTraCTs
consultant/employee for; Company/Drug; Merck. J. Chodakewitz:
2. I am a paid consultant/employee for; Company/Drug; Merck.
J. Wagner: 2. I am a paid consultant/employee for; Company/
Drug; Merck. G. Murphy: 2. I am a paid consultant/employee for;
Company/ Drug; Merck.
BACKGROUND: Orexin neuropeptides play a critical role in regulating
the transition between wake and sleep. Suvorexant (MK-4305),
a potent dual orexin receptor antagonist, represents a potentially new
approach to treating insomnia.
METHODS: This was a multi-part first-in-human study of suvorexant
in healthy young men. Part I was a single rising-dose study to
evaluate the safety, tolerability, and PK of suvorexant (n=16). Part II
was a 4-period crossover study to evaluate the effects of suvorexant on
quantitative EEG (qEEG) (n=12).
RESULTS: Suvorexant was generally well tolerated in healthy
young men up to 120mg with the most frequently reported adverse
experience being somnolence. Following AM administration, suvorexant
was rapidly absorbed with a median T max of 1.0-2.0-hour and
apparent terminal T 1/2 of 8.5-15-hours. Night-time administration did
not affect AUC 0-∞ , but slightly decreased C max and median T max was
delayed by 1-hour. The increases on AUC 0-∞ and Cmax appeared less
than dose proportional from 4 to 120mg. There was a dose-dependent
increase in sleepiness on Karolinska sleepiness scale and decrease in
alertness on Bond-Lader VAS, which were consistent with the desired
PD effects. Following AM administration of 20 and 80mg, suvorexant
produced a dose-dependent increase in delta power spectral density on
qEEG suggesting sleep promoting effects. These effects disappeared at
8 and 12-hour post-dose indicating no long-lasting effect which may
cause next-day residual effects.
CONCLUSION: Suvorexant was well tolerated and demonstrated
PK and PD profiles supporting its development as a hypnotic.
PI-60
NO ADVERSE IMPACT OF REPEATED ORAL DOSES OF
TERIFLUNOMIDE ON THE PHARMACOKINETICS OF ORAL
CONTRACEPTIVE STEROIDS (ETHINYLESTRADIOL AND
LEVONORGESTREL) IN YOUNG HEALTHY FEMALE SUB-
JECTS. S. Turpault, 1 B. Miller, 1 F. Menguy-Vacheron 2 ; 1 Sanofi-
Aventis, Bridgewater, NJ, 2 Sanofi-Aventis, Chilly-Mazarin, France.
S. Turpault: None. B. Miller: None. F. Menguy-Vacheron: None.
BACKGROUND: Teriflunomide is a novel oral disease modifier in
development for relapsing forms of multiple sclerosis (RMS). The aim
of this study was to assess the effect of teriflunomide on pharmacokinetic
(PK) of oral contraceptive combination, ethinylestradiol (ETH)
and levonorgestrel (LEV). Safety was also evaluated.
METHODS: 24 young healthy females were enrolled in a 2-period,
2-treatment study. Period 1 (Days 1-21) comprised daily treatment with
Minidril ® (0.03 mg ETH and 0.15 mg LEV) followed by a 7-day washout.
During Period 2, subjects received Minidril ® (Days 1-21) and teriflunomide
(Days 8-21; 70 mg/day for 4 days followed by 14 mg/day
for 10 days). This was followed by 11 days of cholestyramine, which
accelerates the elimination of teriflunomide. Plasma concentrations of
ETH, LEV and teriflunomide were determined using validated methods.
PK parameters were calculated. Safety evaluations were based on
clinical laboratory tests, vital signs and ECG parameters.
RESULTS: Teriflunomide administration resulted in 1.58- and
1.54-fold increases in C max and AUC 0-24 of ETH, respectively. Similarly,
teriflunomide administration resulted in 1.33- and 1.41-fold
increases in C max and AUC 0-24 of LEV, respectively. No serious treatment-emergent
adverse events (TEAEs) were reported and no subject
discontinued treatment due to TEAEs. 9/24 subjects treated with Minidril
® alone experienced TEAEs (mainly nasopharyngitis (5 subjects)
and headache (3 subjects), while 8/23 subjects receiving teriflunomide
and Minidril ® concomitantly reported TEAEs of nervous system disorders
(5 subjects: mostly headache) and gastrointestinal disorders
(4 subjects).
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aBsTraCTs nature publishing group
CONCLUSION: Teriflunomide was safe and well tolerated when
given with Minidril ® . A modest increase (< 1.6-fold) in ETH and LEV
exposure was observed when coadministered to teriflunomide; therefore,
teriflunomide is not expected to adversely impact the efficacy of
oral contraceptives.
PI-61
GENOTYPE-BASED IN VITRO-IN VIVO EXTRAPOLATION
(IVIVE) OF EFAVIRENZ PHARMACOKINETICS USING A PHYS-
IOLOGICALLY-BASED PHARMACOKINETIC MODEL. C. Xu, 1
S. Quinney, 2 Y. Guo, 3 Z. Desta 1 ; 1 Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, 2 Department
of Obstetrics and Gynecology, Indiana University School of Medicine,
Indianapolis, IN, 3 Drug Disposition, Lilly Research Laboratories,
Indianapolis, IN. C. Xu: None. S. Quinney: None. Y. Guo: None. Z.
Desta: None.
BACKGROUND: The CYP2B6*6 allele is significantly associated
with reduced efavirenz metabolism. We developed a physiologicallybased
pharmacokinetic model (PBPK) for in vitro-in vivo extrapolation
(IVIVE) of efavirenz pharmacokinetics using in vitro data.
METHODS: Cl int for efavirenz 7- and 8-hydroxylation was estimated
from human liver microsomes (HLMs) genotyped for CYP2B6*6
allele (n=5 for each genotype), expressed CYP2B6.1 and CYP2B6.6.
Efavirenz pharmacokinetics of 1000 virtual healthy subjects was simulated
using Cl int for individual HLMs and expressed enzymes by Simcyp
® Population-based Simulator (Version 11). Simulated efavirenz
pharmacokinetics for individuals with each genotype were compared to
the pharmacokinetics of a single 600 mg oral dose of efavirenz administered
to healthy volunteers genotyped for CYP2B6*6 allele (n=20).
RESULTS: The observed and predicted T max , C max , AUC 0-72h and
CL po are shown in the Table. Most measured efavirenz concentrationtime
profiles were within 5th and 95th percentile of concentrations
simulated by a full PBPK model with compartmental absorption transit
model for each genotype. All the predicted pharmacokinetic parameters
were within 2-fold of observed values. CYP2B6*6/*6 was associated
with lower CL po (40~70 %) and higher AUC 0-72h (10~20 %)
compared to wild type.
CONCLUSION: This PBPK model may be valuable for predicting
the impact of CYP2B6 variants on pharmacokinetics from in vitro Cl int
data. Further refinement of this model is ongoing.
Table: Clinical and simulated pharmacokinetic parameters for a single 600 mg
oral dose of efavirenz
T max (h) C max (mg/L) AUC 0-72h (mg/L•h) CL po (L/h)
In vitro
System
Observed Predicted Observed Predicted Observed Predicted Observed Predicted
CYP2B6
*1/*1
HLM
2.3±1.0 2.0±0.4 2.3±0.7 1.79±0.39 45.9±16.7 35.0±15.8 8.5±3.4 9.65±23.3
CYP2B6.1 2.1±0.4 1.90± 0.3 37.2±13.2 4.4±3.3
CYP2B6
*1/*6
HLM
2.6±1.7 2.1±0.41 1.7±0.5 1.86±0.34 40.7±12.2 37.7±15.0 8.3± 2.8 5.3±9.1
CYP2B6
*6/*6
HLM
2.7±1.5 2.1±0.4 2.4±0.2 1.90±0.3 57.3±4.1 41.8±14.5 5.9± 0.5 2.2±2.1
CYP2B6.6 2.1±0.41 1.90±0.31 39.5±13.7 3.1±2.1
All the value presented as mean±S.D.
PI-62
POPULATION PHARMACOKINETICS OF SM-26000, LIPO-
SOMAL AMPHOTERICIN B, IN JAPANESE PEDIATRIC PATIENTS
WITH INVASIVE FUNGAL INFECTION. Y. Ohata, 1 Y. Tomita, 1 K.
Suzuki, 1 T. Maniwa, 1 Y. Yano, 2 K. Sunakawa 3 ; 1 Dainippon Sumitomo
Pharma Co., Ltd., Osaka, Japan, 2 Kyoto Pharmaceutical University,
Kyoto, Japan, 3 Kitasato University, Tokyo, Japan. Y. Ohata: 2. I am a
paid consultant/employee for; Company/Drug; Dainippon Sumitomo
Pharma Co., Ltd. Y. Tomita: 2. I am a paid consultant/employee for;
Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. K. Suzuki: 2.
I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo
Pharma Co., Ltd. T. Maniwa: 2. I am a paid consultant/employee
for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. Y. Yano:
2. I am a paid consultant/employee for; Company/Drug; Dainippon
Sumitomo Pharma Co., Ltd. K. Sunakawa: 2. I am a paid consultant/
employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd.
BACKGROUND: SM-26000 was the encapsulation of Amphotericin
B (AMB) into liposomes (L-AMB). Though antifungal efficacy of AMB
encompasses a broad spectrum of medically important fungal pathogens,
its toxicity was a great problem. The reduced toxicity of the liposomal
formulation allows for the administration of much higher doses of AMB
than can be safely administered when given as conventional AMB, leading
to the expanding therapeutic potential of L-AMB. The objectives of
this study were to develop a population pharmacokinetic (PK) model of
AMB and to simulate PK profiles and to calculate C max,ss /MIC which is
a pharmacokinetic/pharmacodynamic parameter.
METHODS: The PK data at once-daily doses of L-AMB 1.0 mg,
2.5 mg, and 5.0 mg were available. L-AMB was administered by
infusion for 60-120 min. In totality 159 serum concentrations from
39 pediatric patients with invasive fungal infection who were enrolled
in a post-marketing clinical study conducted in Japan were used for
population PK analysis. Model suitability for simulation was confirmed
by visual predictive check based on the 95% prediction intervals which
were calculated using highest posterior density (HPD) region method.
RESULTS: The AMB plasma concentration - time data in Japanese
pediatric patients was described by a two-compartment pharmacokinetics
model with zero-order input and first-order elimination. Among
the candidates for covariates, body weight showed a significant correlation
with CL and Vc. The 95% prediction intervals of inter-individual
variability of virtual patients were consistent with observed values. As
bacterial strains were isolated from some patients, C max,ss /MIC was
estimated as 0.7-33.8, using MIC of each isolate against L-AMB.
CONCLUSION: The development of this population PK model for
L-AMB supported individual subject exposure estimation for population
PK/PD efficacy and safety analysis in the post-marketing clinical study.
PI-63
LOW DENSITY LIPOPROTEIN (LDL-C) EXPOSURE-
RESPONSE ANALYSIS FOR TOFACITINIB (CP-690,550) IN
PATIENTS WITH RHEUMATOID ARTHRITIS. S. P. Riley, M. G.
Boy, R. Riese, S. Krishnaswami; Pfizer, Inc, Groton, CT. S.P. Riley:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am
a significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be
discussing the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). M.G. Boy: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder for;
Company/Drug; Pfizer Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
R. Riese: 1. This research was sponsored by; Company/Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). S. Krishnaswami:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am
a significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be
discussing the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus kinase
(JAK) inhibitor currently in development for treatment of rheumatoid
arthritis (RA). Objectives were to characterize the relationship
between tofacitinib exposure and changes in LDL-c and explore covariate
effects on the exposure-response (ER) relationship.
s30 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
METHODS: LDL-c data from 5 double-blind Phase 2 studies
investigating the efficacy and safety of 1-30 mg BID tofacitinib and
placebo in patients with RA were pooled and analyzed using NON-
MEM 6.2. The ER relationship was described using a longitudinal,
nonlinear mixed-effects model. The structural model form was an indirect
response model with tofacitinib inhibiting the LDL-c elimination
rate. Results were compared with observations from Phase 3 and long
term extension (LTE) studies.
RESULTS: The analysis included 1474 patients with 6106 LDL-c
observations. The model estimated a steady-state ED 50 of 3.6 mg
BID. Mean maximal LDL-c increases were predicted to be reached in
approximately 5 weeks, with no evidence of a progressive increase for
treatment durations of up to 3 years in LTE studies. Covariate analysis
suggested that age, body weight, diabetic status, and race influenced
baseline LDL-c. Subjects with hyperlipidemia at baseline showed
smaller maximal increases (E max ) in LDL-c compared to patients with
normal baseline. Subjects achieving ≥ 50% improvement in signs and
symptoms of RA (American College of Rheumatology (ACR) 50)
showed modestly larger E max compared to those who did not. Consistent
with Phase 3 study observations, doses of 5 mg and 10 mg BID
tofacitinib were estimated to have mean (90% CI) LDL-c increases
from baseline of 13.4% (9.3-17.8) and 18.1% (12.9-24.9) respectively,
at steady state.
CONCLUSION: Model predictions based on Phase 2 study data
suggest that the time course and magnitude of LDL-c increases following
treatment with tofacitinib in RA patients are predictable and
concordant with Phase 3 and LTE study observations.
PI-64
A PHASE 1 STUDY TO ESTIMATE THE EFFECT OF KETO-
CONAZOLE ON THE PHARMACOKINETICS OF TOFACITINIB
(CP-690,550) IN HEALTHY VOLUNTEERS. P. Gupta, 1 R. Wang, 1
I. Kaplan, 1 C. W. Alvey, 1 M. Ndongo, 2 S. Krishnaswami 1 ; 1 Pfizer
Inc, Groton, CT, 2 Pfizer Clinical Research Unit, Brussels, Belgium.
P. Gupta: 1. This research was sponsored by; Company/Drug; Pfizer
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer
Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer Inc.
6. I will be discussing the following product, which is not labeled
for the use under discussion, or the product is still investigational;
Company/ Drug; Tofacitinib (CP-690,550). R. Wang: 1. This research
was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under discussion,
or the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). I. Kaplan: 1. This research was sponsored by;
Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
C.W. Alvey: 1. This research was sponsored by; Company/Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 5. I am a significant stockholder for; Company/Drug;
Pfizer Inc as part of my employee 401 (K) benefit. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). M. Ndongo: 1. This research was sponsored
by; Company/ Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
S. Krishnaswami: 1. This research was sponsored by; Company/Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer
Inc. 6. I will be discussing the following product, which is not labeled
for the use under discussion, or the product is still investigational;
Company/ Drug; Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus
kinase (JAK) inhibitor currently in development for the treatment
aBsTraCTs
of several inflammatory diseases including rheumatoid arthritis and
psoriasis. The objective of this study was to estimate the effect of
ketoconazole oral administration on the PK of a single 10 mg oral
dose of tofacitinib.
METHODS: This study was an open label, single fixed sequence
study (A3921054; NCT01202240) in 12 healthy male subjects who
received: (a) single dose oral tofacitinib 10 mg in Period 1 and (b)
single dose oral tofacitinib 10 mg following 3 days of ketoconazole
(400 mg qd) treatment in Period 2. Tofacitinib PK samples were
collected prior to dosing (0 hours) and post-dose at 0.5, 1, 2, 4, 6, 8,
12, 16, and 24 hours in Periods 1 (Days 1) and 2 (Days 3 and 4). PK
parameters were calculated using noncompartmental analysis. The
interactive effect on PK parameters was determined by analysis of
variance which was used to calculate adjusted geometric mean ratios
for test/reference (coadministration/tofacitinib alone) and the associated
90% confidence intervals.
RESULTS: Coadministration with ketoconazole increased AUC inf
and C max by 103%, and 16%, respectively. The ratio of adjusted geometric
means was 203.23% (90% CI: 190.96%, 216.30%) for AUCinf
and 116.24% (90% CI: 104.59%, 129.18%) for Cmax. Mean terminal
t1/2 increased from 2.9 hours for tofacitinib alone to 3.9 hours for
tofacitinib with ketoconazole. Median Tmax increased from 0.5 hours
for tofacitinib alone to 1.0 hours with ketoconazole.
CONCLUSION: The observed approximate doubling of tofacitinib
AUCinf with ketoconazole is consistent with predictions from in-vitro
data (~55% contribution by CYP3A4-mediated metabolism to total
clearance) and suggests that tofacitinib dose may need to be adjusted
or restricted when coadministered with ketoconazole.
PI-65
NONLINEAR MIXED-EFFECTS MODELING OF THE INTER-
SPECIES PHARMACOKINETIC SCALING OF CEFADROXIL
AFTER ORAL AND INTRAVENOUS BOLUS ADMINISTRATION.
M. M. Posada, D. Smith, M. Feng; University of Michigan, Ann Arbor,
MI. M.M. Posada: None. D. Smith: None. M. Feng: None.
BACKGROUND: The purpose of this study was to use an allometric
scaling approach to predict human pharmacokinetic parameters
of cefadroxil using animal pharmacokinetic data after oral and bolus
I.V. dosing. Cefadroxil, a first generation cephalosporin, has high bioavailability
and is excreted unchanged in urine. Its absorption and
elimination are dependent on transporters, such as PEPT1 in the small
intestine, and PEPT2 and OATs in the kidney.
METHODS: The pharmacokinetic data used in this work were collected
from the literature (mouse, rat, and horse) and from our own
experiments performed in wild-type mice. The data were analyzed
using different models, and the best one was chosen based on the goodness
of fit. The data were pooled together and analyzed using mixedeffects
modeling (NONMEM), and the results obtained were validated
using a set of human data obtained from the literature.
RESULTS: The pharmacokinetics of cefadroxil is best described
by one-compartment model following I.V. or oral administration.. The
allometry predicted human clearance (CL or CL/F), volume of distribution
(V or V/F) and absorption rate constant (ka) were within 2-fold
of the literature values. The maximum lifespan potential and/or body
weight were used as covariates in the allometry model. Different error
models were compared, and a proportional error model was selected
based on the statistics. The predicted human CL and V are 101 ml/
min and 36.7 L, respectively, based on IV dose data from mice, rats,
and foals. However, only the mouse data were used for the prediction
of human oral PK because the absorption in rats and foals was significantly
slower compared to humans and mice. The predicted human
CL/F, V/F, and ka were 215 mL/min, 31.3 L, and 0.03min -1 , respectively.
CONCLUSION: Our models allowed a good prediction of the
pharmacokinetic parameters of cefadroxil in humans showing that
interspecies scaling is a useful tool in the extrapolation from animals
to humans.
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aBsTraCTs nature publishing group
PI-66
SIMULTANEOUS PHARMACOKINETIC MODELING OF
WR-1065 IN BLOOD AND TISSUES USING NONLINEAR MIXED
EFFECTS MODELING AND EXTRAPOLATION FROM RATS TO
HUMANS WITH BODY WEIGHT AS A COVARIATE. M. R. Feng, 1
X. Chen, 1 M. Hutchmatt, 2 Z. Lu, 3 B. Yang, 1 D. Smith 1 ; 1 University of
Michigan, Ann Arbor, MI, 2 The Ann Arbor Pharmacometrics Group,
Ann Arbor, MI, 3 AstraZeneca Pharmaceuticals, Wilmington, DE.
M.R. Feng: None. X. Chen: None. M. Hutchmatt: None. Z. Lu:
None. B. Yang: None. D. Smith: None.
BACKGROUND: Amifostine is a thiophosphate prodrug selectively
protecting normal tissues and used in several clinical trials for
protecting normal tissues. Amifostine is rapidly metabolized in the
body and converted to its active metabolite (WR-1065) by alkaline
phosphatase. Since the metabolite WR-1065 is mainly associated with
the key cytoprotective effects, the objective of our study is to develop a
population pharmacokinetic (PK) model for simultaneous quantitation
of WR-1065 in blood, liver and tumor tissues in rats and to extrapolate
the model to humans to assist the prediction of WR-1065 concentration-time
profile in blood and key human tissues associated with efficacy
or adverse effects to help optimize the dose and dose-regimen in
clinical therapy.
METHODS: Human blood samples were collected from cancer
patients treated with liver radiation and intravenous amifostine. Rat
blood and tissue samples were collected following intravenous doses
of amifostine to rats with intrahepatic tumor. Pharmacokinetic modeling
was performed using Nonlinear Mixed Effects Modeling (NON-
MEM).
RESULTS: WR-1065 PK profiles in rats are best described by a
4-compartment model with predicted values similar to the actual concentrations
in blood, liver, and tumor. The extrapolation from rat to
human was successfully performed using body weight as a covariate
and the predicted PK profiles are highly correlated with the actual
blood levels.
CONCLUSION: NONMEM was successfully applied to the simultaneous
modeling of WR-1065 in blood and tissues in rats and the
extrapolation from animals to humans.
PI-67
CHARACTERIZATION OF THE RELATIONSHIP BETWEEN
IPILIMUMAB EXPOSURE, TUMOR SIZE, AND SURVIVAL IN
PREVIOUSLY UNTREATED NON-SMALL CELL LUNG CANCER
PATIENTS. Y. Feng, 1 E. Masson, 1 D. Williams, 1 J. Song, 2 J. Cuillerot, 2
A. Roy 1 ; 1 Bristol-Myers Squibb Co., Princeton, NJ, 2 Bristol-Myers
Squibb Co., Wallingford, CT. Y. Feng: None. E. Masson: None.
D. Williams: None. J. Song: None. J. Cuillerot: None. A. Roy: None.
BACKGROUND: Ipilimumab is a fully human monoclonal
antibody directed against cytotoxic T-lymphocyte antigen-4 that
is approved in FDA, EU and Australia for treatment of advanced
melanoma. It is also being developed for the treatment of other solid
tumors. The analysis aims to investigate the relationships between
ipilimumab exposure, tumor responses and overall survival (OS) in
previously untreated Non-Small Cell lung cancer (NSCLC) patients.
METHODS: The retrospective analysis was conducted with data
from 187 NSCLC patients in a double-blinded, randomized Phase
2 study (CA184041) of ipilimumab 10 mg/kg in combination with
chemotherapy (paclitaxel/carboplatin) compared to chemotherapy
alone. Longitudinal tumor size data was characterized by a parametric
mixed-effect model. The relationship between tumor shrinkage
and OS was characterized by a parametric survival model. The impact
of ipilimumab schedule of administration/dose/exposure (Cminss
and Cavgss) and the following covariates on model parameters were
assessed: ECOG status, baseline lactate dehydrogenase levels, percent
of tumor size change from baseline at week 6, 8 and 12 (PT6, PT8 and
PT12), and baseline tumor size.
RESULTS: Tumor shrinkage rate was similar across all treatment
arms, however, tumor progression rate was lower in patients who
received ipilimumab contained therapy compared to those receiving
chemotherapy alone. PT8 was a better predictor of OS than PT6
and PT12. The risk of death decreased with higher tumor reduction
(PT8), increased with increasing baseline tumor size, and was higher
in patients with ECOG status > 0.
CONCLUSION: Tumor progression appears to be slower in
patients receiving ipilimumab and PT8 appears to be a good predictor
of OS in immunotherapy of ipilimumab in NSCLC patients.
PI-68
INVESTIGATION OF THE ELIMINATION OF DABIGAT-
RAN BY HAEMODIALYSIS IN PATIENTS WITH END STAGE
RENAL DISEASE (ESRD). S. Haertter, 1 M. Trenmmel, 1 G. Nehmiz, 2
K. Liesenfeld, 1 V. Moschetti, 1 H. Peters, 3 F. Wagner, 4 S. Formella 5 ;
1 Boehringer Ingelheim Pharma, Translational Medicine, Germany,
2 Boehringer Ingelheim Pharma, Biberach, Germany, 3 Department of
Nephrology, Charite, Berlin, Germany, 4 Charite Research Organization,
Berlin, Germany, 5 Boehringer Ingelheim Pharma, Ingelheim,
Germany. S. Haertter: 1. This research was sponsored by; Company/
Drug; Boehringer Ingelheim Pharma GmbH & Co. KG. 2. I am a paid
consultant/employee for; Company/Drug; Boehringer Ingelheim
Pharma GmbH & Co. KG. M. Trenmmel: 2. I am a paid consultant/employee
for; Company/Drug; Boehringer Ingelheim Pharma
GmbH & Co. KG. G. Nehmiz: 2. I am a paid consultant/employee for;
Company/ Drug; Boehringer Ingelheim Pharma GmbH & Co. KG.
K. Liesenfeld: 2. I am a paid consultant/employee for; Company/
Drug; Boehringer Ingelheim Pharma GmbH & Co. KG. V. Moschetti:
2. I am a paid consultant/employee for; Company/Drug; Boehringer
Ingelheim Pharma GmbH & Co. KG. H. Peters: 1. This research was
sponsored by; Company/Drug; Boehringer Ingelheim Pharma GmbH
& Co. KG. F. Wagner: 1. This research was sponsored by; Company/
Drug; Boehringer Ingelheim Pharma GmbH & Co. KG. S. Formella:
2. I am a paid consultant/employee for; Company/Drug; Boehringer
Ingelheim Pharma gmbH & Co KG.
BACKGROUND: Dabigatran etexilate (DE) is a pro-drug which
is rapidly converted by esterases to the active moiety dabigatran (D),
a direct thrombin inhibitor. D is cleared to > 80% renally and hence
haemodialysis may be an approach to efficiently remove dabigatran
from the body.
METHODS: Open-label, fixed-sequence, 2-period trial with a
wash-out phase of at least 6 weeks between treatments in 7 ESRD
subjects who required regular haemodialysis . In each trial period, DE
was administered at descending dosages of 150 mg, 110 mg and
75 mg q.d. on days 1, 2, and 3, respectively. The dialysis was initiated
8h after the morning dose on day 3 of each period, lasting for 4h with
an increase in blood flow rate (BFR) from 200 mL/min (period 1) to
400 mL/min (period 2). Plasma concentrations of total D (= D + active
D-glucuronide) were measured by LC-MS/MS. Pharmacodynamic
(PD) endpoints were activated partial thromboplastin time (aPTT) and
Factor IIa inhibition. All PK, PD, and safety endpoints were analyzed
using descriptive statistical methods.
RESULTS: D geometric Mean, gMean, peak concentration at
the days of dialysis were 176 ng/mL and 159 ng/mL in period 1 and
2. Heamodialysis resulted in a gMean reduction of total D concentration
by 48.8% (gCV=10.9%) and 59.3% (gCV = 6.69%) in period 1
and 2, respectively. An approximate doubling of the BFR increased
dialysis clearance of total D from blood by approximately 50%
(gMean 161 mL/min (gCV = 5.01%) vs. 241 mL/min (gCV = 3.08%).
The re-distribution effect after dialysis was marginal (concentration
post dialysis was elevated on average by 7.52% and 15.5%, in period1
and 2, respectively). Dialysis did not affect the PK/PD relationship. No
deaths, serious AEs, other significant AEs, or AEs of severe intensity
were reported.
CONCLUSION: The haemodialysis procedures employed in the
trial resulted in substantial clearance of total plasma D, reducing the
pharmacodynamic effect of D. Dialysis clearance of D was higher for
higher dialysis BFR.
s32 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
PI-69
PHARMACOKINETIC (PK) ANALYSIS OF COADMINISTRA-
TION OF AXITINIB AND PEMETREXED/CISPLATIN (PEM/
CIS) IN PATIENTS WITH NON-SMALL CELL LUNG CANCER
(NSCLC). M. A. Tortorici, 1 L. Iglesias, 2 M. F. Kozloff, 3 Y. K.
Pithavala, 1 A. Ingrosso, 4 C. P. Belani 5 ; 1 Pfizer Oncology, San Diego,
CA, 2 Hospital Doce de Octubre, Madrid, Spain, 3 Ingalls Hospital,
Harvey, IL, 4 Pfizer Italia Srl, Milano, Italy, 5 Penn State Hershey Cancer
Institute, Hershey, PA. M.A. Tortorici: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee for;
Company/Drug; Pfizer Inc. L. Iglesias: None. M.F. Kozloff: None.
Y.K. Pithavala: 2. I am a paid consultant/employee for; Company/
Drug; Pfizer Inc. A. Ingrosso: 2. I am a paid consultant/employee for;
Company/Drug; Pfizer Inc. C.P. Belani: 2. I am a paid consultant/
employee for; Company/Drug; Pfizer Inc.
BACKGROUND: Axitinib (AG-013736 [AG]) is an oral, potent,
and selective second-generation inhibitor of vascular endothelial
growth factor receptors 1, 2, and 3 with clinical activity against several
solid tumors, including NSCLC. AG was added to the chemotherapy
regimen of pem/cis for its additive improvement in efficacy. The objectives
of this study were to determine the PK of AG and pem/cis and
identify the appropriate dose of AG to combine with pem/cis for treatment
of advanced NSCLC.
METHODS: PK data from two studies of AG evaluated the combination
with pem/cis: a phase I study in patients with solid tumors
(n = 4) and a phase I lead-in portion of a phase II study in patients with
advanced nonsquamous NSCLC (n=10). AG 5 mg BID was administered
during the lead-in period of 3 to 5 days and continued to Day (D)
18. After a 5-day interruption, AG was resumed on Cycle (C) 2 D3.
Pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) were given on
C1D1 and every 3 weeks thereafter. Serial blood draws were collected
on D -1 (AG), C1D1 (AG + pem/cis), and C2D1 (pem/cis). PK parameters
were estimated using non-compartmental methods.
RESULTS: PK parameters were similar for AG in the absence and
presence of pem/cis. The mean (%CV) AG area under the plasma-concentration
time curve from 0 to 24 h (AUC 24 ) was 344 (57) and 386 (51)
ng·hr/mL in the absence and presence of pem/cis, respectively. In addition,
PK parameters were similar for pem/cis in the absence and presence
of AG, respectively: mean (%CV) pemetrexed AUC inf was 147 (17) and
157 (17) μg·hr/mL and mean (%CV) AUC 8 for total platinum in plasma
ultrafiltrate (PUF) was 2470 (26) and 2808 (29) μg·hr/mL.
CONCLUSION: At 5 mg BID dose of AG and full doses of pem/
cis, the PKs of the three drugs are not altered when administered alone
or in combination.
PI-70
SINGLE AND MULTIPLE-DOSE PHARMACOKINETICS
OF TOFACITINIB (CP-690,550) FROM A DOUBLE-BLIND,
PLACEBO-CONTROLLED, DOSE-ESCALATION STUDY IN
MEDICALLY STABLE SUBJECTS WITH PSORIASIS. S. Menon,
M. G. Boy, C. Wang, B. E. Wilkinson, S. H. Zwillich, G. Chan, S.
Krishnaswami; Pfizer Inc, Specialty Care Business Unit, Groton,
CT. S. Menon: 1. This research was sponsored by; Company/Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). M.G. Boy: 1. This
research was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid
consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a significant
stockholder for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). C. Wang: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder for;
Company/Drug; Pfizer Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
aBsTraCTs
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
B.E. Wilkinson: 1. This research was sponsored by; Company/Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer
Inc. 6. I will be discussing the following product, which is not labeled for
the use under discussion, or the product is still investigational; Company/
Drug; Tofacitinib (CP-690,550). S.H. Zwillich: 1. This research was
sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/
employee for; Company/Drug; Pfizer Inc. 6. I will be discussing the
following product, which is not labeled for the use under discussion,
or the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). G. Chan: 1. This research was sponsored by; Company/
Drug; Pfizer Inc. 2. I am a paid consultant/employee for; Company/
Drug; Pfizer Inc. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). S. Krishnaswami:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a
significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus Kinase
(JAK) inhibitor currently in development for the treatment of several
inflammatory diseases including rheumatoid arthritis and psoriasis. An
objective of this study was to characterize the single and multiple dose
pharmacokinetics (PK) of tofacitinib.
METHODS: This study (A3921003) was an investigator and subject-blinded,
sponsor-open, parallel group, placebo-controlled, multiple
dose escalation study in 59 medically stable subjects with psoriasis.
Multiple doses of 5 to 50 mg twice-daily (BID) and 60 mg once-daily
(QD) were evaluated over 14 days. Doses of 5, 10, 20 and 30 mg BID
were administered using oral powder for constitution (OPC), and 50 mg
BID and 60 mg QD doses were administered as tablets. Serial blood
and urine samples were collected on Day 1 and on Day 14. PK parameters
were calculated using standard noncompartmental methods.
RESULTS: Upon single and multiple dosing, mean systemic exposure
parameters (C max and AUC) of tofacitinib increased in an approximately
dose proportional manner. T max generally occurred at 0.5 to
1 hour, and mean apparent terminal elimination phase half-lives ranged
between 2.3 to 4.3 hours. Across the dose groups the mean Day 14/Day
1 ratio of AUC(0-tau) ranged between 0.974 to 1.62, with an overall
geometric mean accumulation ratio of approximately 1.1. The mean
percent of administered dose excreted unchanged in urine ranged from
18.3% to 27.2% across the dose range.
CONCLUSION: The PK profile of tofacitinib is characterized by
rapid absorption, rapid elimination and dose proportional pharmacokinetics
over a wide dose range. Steady state concentrations are achieved
rapidly, with minimal accumulation after BID administration.
PI-71
THE EFFECT OF TOFACITINIB (CP-690,550) ON THE PHAR-
MACOKINETICS OF ORAL CONTRACEPTIVE STEROIDS
IN HEALTHY FEMALE VOLUNTEERS. S. Menon, 1 R. Riese, 1
R. Wang, 1 C. W. Alvey, 1 W. Petit, 2 S. Krishnaswami 1 ; 1 Pfizer Inc, Groton,
CT, 2 Pfizer Clinical Research Unit, Brussels, Belgium. S. Menon:
1. This research was sponsored by; Company/Drug; Pfizer Inc.
2. I am a paid consultant/employee for; Company/Drug; Pfizer Inc.
6. I will be discussing the following product, which is not labeled for
the use under discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). R. Riese: 1. This research was
sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/
employee for; Company/Drug; Pfizer Inc. 6. I will be discussing the
following product, which is not labeled for the use under discussion,
or the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). R. Wang: 1. This research was sponsored by; Company/Drug;
Pfizer. 2. I am a paid consultant/employee for; Company/
Drug; Pfizer Inc. 6. I will be discussing the following product, which
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s33

aBsTraCTs nature publishing group
is not labeled for the use under discussion, or the product is still investigational;
Company/ Drug; Tofacitinib (CP-690,550). C.W. Alvey:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a
significant stockholder for; Company/Drug; Pfizer Inc as part of my
employee 401 (K) benefit. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
W. Petit: 1. This research was sponsored by; Company/Drug; Pfizer
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer
Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer Inc,
not significant. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). S. Krishnaswami:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am
a significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be
discussing the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus Kinase
(JAK) inhibitor currently in development for the treatment of several
inflammatory diseases including rheumatoid arthritis and psoriasis.
The objective of this study was to demonstrate a lack of an inhibitive or
inductive effect of tofacitinib on the pharmacokinetics (PK) of the oral
contraceptives (OCs), ethinyl estradiol (EE) and levonorgestrel (LN).
METHODS: This was a randomized, open-label, 2-sequence,
2-period crossover study (A3921071; NCT01137708) of the effect of
30 mg twice-daily (BID) tofacitinib for 11 days on the single-dose PK
of OCs (administered as a single Microgynon 30 ® tablet) in 19 healthy
female subjects. Blood samples for EE and for LN PK were collected
prior to and up to 48 hours post-dose. PK parameters were calculated
using noncompartmental analysis. Treatment comparisons were made
using analysis of variance to calculate adjusted geometric mean ratios
for test/reference and associated 90% confidence intervals for the mean
ratios. The test and reference treatments were OC treatments with and
without coadministration of tofacitinib, respectively.
RESULTS: The 90% CIs for the ratios of the adjusted geometric
means (Test/Reference) for AUC inf and C max were entirely within the
predefined acceptance region (80.00%, 125.00%) for both EE and LN
when single oral doses of the combination OCs were administered with
multiple-dose tofacitinib relative to the OCs administered alone, indicating
that tofacitinib had no net inhibitive or inductive effect on the
PK of EE and LN. For both agents, t 1/2 and T max values were similar
with and without coadministration of tofacitinib.
CONCLUSION: Tofacitinib does not influence the PK of oral contraceptives,
ethinyl estradiol and levonorgestrel.
PI-72
EFFECTS OF QUINIDINE ON PHARMACOKINETICS (PK)
OF ORAL (PO) AND INTRAVENOUSLY (IV) ADMINISTERED
EDOXABAN. N. Matsushima, 1 J. Mendell, 1 H. Zahir, 1 F. Lee, 2
T. Sato, 1 J. Jin, 1 D. Weiss 2 ; 1 Daiichi Sankyo, Co, Ltd, Parsippany, NJ,
2 Celerion, Inc, Neptune, NJ. N. Matsushima: 1. This research was
sponsored by; Company/Drug; Daiichi Sankyo, Inc. 2. I am a paid
consultant/employee for; Company/Drug; Daiichi Sankyo Co., Ltd.
6. I will be discussing the following product, which is not labeled for
the use under discussion, or the product is still investigational; Company/Drug;
Edoxaban [still investigational]. J. Mendell: 1. This
research was sponsored by; Company/Drug; Daiichi Sankyo, Inc. 2.
I am a paid consultant/employee for; Company/Drug; Daiichi Sankyo
Co., Ltd. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. H. Zahir:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is still
investigational; Company/Drug; Edoxaban [still investigational].
F. Lee: 1. This research was sponsored by; Company/Drug; Daiichi
Sankyo, Inc. 2. I am a paid consultant/employee for; Company/Drug;
Celerion, Inc. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. T. Sato:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 6. I will be discussing the following product, which
is not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. J. Jin:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 5. I am a significant stockholder for; Company/
Drug; Daiichi Sankyo, Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; Edoxaban [still investigational].
D. Weiss: 1. This research was sponsored by; Company/Drug; Daiichi
Sankyo, Inc. 2. I am a paid consultant/employee for; Company/Drug;
Celerion, Inc. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational].
BACKGROUND: Edoxaban is a selective, oral direct factor Xa
inhibitor currently in phase 3 clinical development for stroke prevention
in atrial fibrillation and the treatment and secondary prevention of
venous thromboembolism. Edoxaban is a substrate of P-glycoprotein
(P-gp), therefore, the effect of quinidine, a potent P-gp inhibitor, on
the absorption and elimination of edoxaban was evaluated in 2 clinical
studies in healthy subjects.
METHODS: The effects of oral quinidine (300 mg, tid) on the
PK of edoxaban were assessed in 2 randomized, open label, crossover
studies: a) Study 1 edoxaban PO 60 mg (n = 42) and b) Study 2
edoxaban IV 30 mg infused over 30 min (n = 36). Blood samples for
PK assessment were collected up to 24 hours and 72 hours post-dose
in the PO and IV dose studies, respectively. The plasma concentrations
of edoxaban and its metabolite, M4, were determined by validated
LC-MS/MS methods. Edoxaban PK was compared by treatments;
edoxaban coadministered with quinidine vs edoxaban alone using a
mixed-effect model.
RESULTS: Based on the geometric LSM ratio values, co-administration
of quinidine increased the total exposure (AUC) of edoxaban by
77% and 35% following PO and IV administration, respectively.
CONCLUSION: Quinidine increases total exposure of PO or IV
edoxaban. These results suggest that P-gp inhibition influences both
the absorption and elimination of edoxaban.
Parameter a
AUC last ,
ng·hr/mL
Geometric
LSM ratio
(90% CI), %
Study 1 (oral edoxaban) Study 2 (IV edoxaban)
Edoxaban
60 mg PO
(n=35)
Edoxaban 60 mg
PO + Quinidine
(n=33)
Edoxaban
30 mg IV
(n=35)
Edoxaban 30 mg
IV + Quinidine
(n=28)
1443 ± 329.7 2484 ± 402.4 1305 ± 189.6 1758 ± 318.1
- 177 (165-189) - 135 (128-143)
C max , ng/mL 223 ± 74.9 390 ± 93.4 424 ± 114.8 456 ± 132.5
Geometric
LSM ratio
(90% CI), %
- 185 (165-208) - 107 (96-120)
T max , h b 1.5 (0.5, 6.0) 1.5 (0.5, 2.5) 0.5 (0.3, 2.0) 0.5 (0.5, 1.0)
t 1/2 , h 6.4 ± 1.59 5.0 ± 0.62 6.7 ± 2.54 11.3 ± 7.82
a Parameters arithmetic mean (± SD) unless indicated; b Median (min, max)
s34 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
PI-73
THE EFFECT OF RIFAMPIN ON THE PHARMACOKINET-
ICS OF TOFACITINIB (CP-690,550) IN HEALTHY VOLUN-
TEERS. M. Lamba, 1 R. Wang, 1 I. Kaplan, 1 J. Salageanu, 1 S. Tarabar, 2
S. Krishnaswami 1 ; 1 Pfizer, Groton, CT, 2 Pfizer Clinical Research
Unit, New Haven, CT. M. Lamba: 1. This research was sponsored
by; Company/ Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
R. Wang: 1. This research was sponsored by; Company/Drug; Pfizer
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer
Inc. 6. I will be discussing the following product, which is not labeled
for the use under discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). I. Kaplan: 1. This research
was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under discussion,
or the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). J. Salageanu: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
S. Tarabar: 1. This research was sponsored by; Company/ Drug;
Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug;
Pfizer Inc. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). S. Krishnaswami:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am
a significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be
discussing the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus kinase
(JAK) inhibitor in development for the treatment of several inflammatory
diseases including rheumatoid arthritis and psoriasis. The objective
of this study was to estimate the effect of repeat-dose, oral rifampin
administration, a potent CYP3A4 inducer, on the pharmacokinetics
(PK) of a single 30 mg oral dose of tofacitinib.
METHODS: This study (A3921056; NCT01204112) was an open
label, 2-period, single fixed sequence study. Twelve healthy subjects
received: (a) single dose oral tofacitinib 30 mg in Period 1 and (b) single
dose oral tofacitinib 30 mg following 7 days of rifampin (600 mg
q24 h) treatment in Period 2. Tofacitinib PK samples were collected
prior to dosing (0 hours) and post-dose at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24
hours in Periods 1 (Days 1) and Period 2 (Day 8). PK parameters were
calculated using noncompartmental analysis. Treatment comparisons
were made using analysis of variance to calculate adjusted geometric
mean ratios for test/reference and associated 90% confidence intervals
for ratios. The test and reference treatments were tofacitinib treatments
with and without coadministration of rifampin, respectively.
RESULTS: Coadministration of rifampin significantly decreased
mean tofacitinib exposure (AUC inf ) by 84% and peak concentration
(C max ) by 74%. The ratio of the adjusted geometric means of
test/reference were 16.10% (90% CI: 14.24% to 18.20%) for AUC inf
and 26.32% (90% CI: 22.63% to 30.61%) for C max . Mean t1/2 for
CP-690,550 decreased from 4.2 hours to 2.9 hours in the presence of
rifampin. Median T max was similar with and without rifampin co-administration.
CONCLUSION: Coadministration of tofacitinib with rifampin
resulted in a decrease in overall tofacitinib plasma exposures, which
may result in loss of or reduced clinical response.
aBsTraCTs
PI-74
THE EFFECT OF FOOD ON THE PHARMACOKINET-
ICS OF TOFACITINIB (CP-690,550). M. Lamba, 1 R. Wang, 1
T. Stock, 2 M. O’Gorman, 1 S. Krishnaswami 1 ; 1 Pfizer Inc, Groton,
CT, 2 Pfizer Inc, Collegeville, PA. M. Lamba: 1. This research was
sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). R. Wang: 1. This research was sponsored
by; Company/ Drug; Pfizer Inc. 2. I am a paid consultant/
employee for; Company/Drug; Pfizer Inc. 6. I will be discussing
the following product, which is not labeled for the use under discussion,
or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550). T. Stock: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). M. O’Gorman: 1. This research was sponsored by;
Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550). S. Krishnaswami: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder
for; Company/Drug; Pfizer Inc. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Tofacitinib
(CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus kinase
(JAK) inhibitor currently in development for the treatment of several
inflammatory diseases including rheumatoid arthritis and psoriasis.
The objective of these studies was to characterize the effect of food on
the pharmacokinetics (PK) of tofacitinib in healthy subjects.
METHODS: Two Phase 1 studies evaluated the effect of food on
tofacitinib PK, one using a 50 mg dose of a tablet used in early clinical
development (A3921005) and the other using a 10 mg dose of
the to-be-marketed tablet (A3921076; NCT01184001). Both studies
were open-label, single dose, crossover studies in healthy subjects.
After an overnight fast, subjects were administered either the FDA
recommended high fat breakfast 30 minutes prior to administration
of tofacitinib with 240 mL of water (fed, test treatment) or with 240
mL of water in fasted state (fasted, reference treatment). PK parameters
were calculated using noncompartmental analysis. Treatment
comparisons were made using a mixed effects model to generate
adjusted geometric mean ratios (fed/fasted) and their 90% confidence
intervals (CIs).
RESULTS: Coadministration of tofacitinib with a high fat meal
had no impact on AUC inf , as the 90% CIs for the ratios of adjusted
geometric means (fed/fasted) were entirely contained within the
80.00-125.00% acceptance limits in both studies. Mean (90% CI)
C max was decreased with food and to a similar extent following both
10 mg (31.8% [90% CI 20.4, 41.6]) and 50 mg (25.8% [18.9, 32.0])
doses. Median T max increased from 0.5 hour under fasted condition to
1-2 hours under fed condition.
CONCLUSION: Coadministration with high fat meal resulted in
no major changes in the systemic exposure of tofacitinib. The magnitude
of decrease in C max is not considered to be clinically relevant.
Therefore, no dosage adjustments or time restrictions between meal
and drug intake are necessary.
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s35

aBsTraCTs nature publishing group
PI-75
A PHARMACOKINETIC STUDY OF ORAL PACLITAXEL IN
COMBINATION WITH HM30181 IN SOLID CANCER PATIENTS.
S. E. Kim, N. Gu, D. Shin, S. H. Yoon, J. Y. Cho, S. G. Shin,
K. S. Yu, I. J. Jang; Department of Clinical Pharmacology and Therapeutics,
Seoul National University College of Medicine and Hospital,
Seoul, Republic of Korea. S.E. Kim: 1. This research was sponsored
by; Company/Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea).
None of the authors have any conflict of interest. N. Gu: 1. This
research was sponsored by; Company/Drug; Hanmi Pharmaceutical
Co., Ltd. (Seoul, Korea). None of the authors have any conflict of
interest. D. Shin: 1. This research was sponsored by; Company/Drug;
Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea). None of the authors
have any conflict of interest. S.H. Yoon: 1. This research was sponsored
by; Company/Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul,
Korea). None of the authors have any conflict of interest. J.Y. Cho:
1. This research was sponsored by; Company/Drug; Hanmi Pharmaceutical
Co., Ltd. (Seoul, Korea). None of the authors have any conflict
of interest. S.G. Shin: 1. This research was sponsored by; Company/
Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea). None of the
authors have any conflict of interest. K.S. Yu: 1. This research was
sponsored by; Company/Drug; Hanmi Pharmaceutical Co., Ltd.
(Seoul, Korea). None of the authors have any conflict of interest.
I.J. Jang: 1. This research was sponsored by; Company/Drug; Hanmi
Pharmaceutical Co., Ltd. (Seoul, Korea). None of the authors have any
conflict of interest.
BACKGROUND: As a selective inhibitor of multi-drug resistance
1, HM30181 have a potential to provide an increase in oral bioavailability
of paclitaxel, a chemotherapeutic agent. The aim of this study was
to explore the pharmacokinetics (PKs) of paclitaxel after oral administrations
of capsule formulations in combination with HM30181AK
tablet in patients with solid cancer.
METHODS: Paclitaxel of 180 mg/m 2 and 240 mg/m 2 was administered
in combination with a HM30181AK 15 mg tablet on day
1 and was administered alone on day 2. Paclitaxel of 300 mg/m 2
was co-administered with a HM30181AK 15 mg tablet on day 1 and
day 2. Blood and urine samples for PK analysis were collected up to
48 hours after the first dose on day 1 in 3 patients per 3 dose groups.
Paclitaxel concentrations were determined by liquid chromatographytandem
mass spectrometry and PK parameters were estimated by noncompartmental
analysis.
RESULTS: The mean (standard deviation) AUC last of paclitaxel on
day 1 was 462.8 (343.9), 993.7 (76.9), and 846.3 (283.1) μg*hr/L and
that on day 2 was 527.2 (431.1), 456.3 (120.4), and 1157.1 (409.7)
μg*hr/L following administration of paclitaxel (180, 240, and 300 mg/
m 2 , respectively); the mean (minimum-maximum) time of paclitaxel
concentrations above 0.01 μM were 17.7 (1.3 - 32.8), 43.2 (33.8 -
48.1), and 47.5 (47.0 - 47.7) hours, respectively. The fraction excreted
unchanged in urine was 1.13, 2.30, and 1.90% on day 1 and that was
1.36, 1.22, and 2.07% on day 2 after administration of 180, 240, and
300 mg/m 2 paclitaxel, respectively.
CONCLUSION: The systemic exposures of paclitaxel were not
proportional to increases in the dose. Among three paclitaxel dose
groups, 300 mg/m 2 group represented the highest sum of AUC last on
day 1 and day 2 and its mean time of paclitaxel concentrations above
0.01 μM was 47.5 hours.
PI-76
DIFFERENCES IN ACUTE PAIN, HYPERALGESIA, ALLODY-
NIA AND NEUROGENIC FLARE IN RESPONSE TO TOPICAL
AND INTRADERMAL CAPSAICIN. K. Francke, 1 E. Neuhoff, 1
W. Heber, 2 J. Lambert, 1 M. Grossmann 3 ; 1 PAREXEL, London, United
Kingdom, 2 PAREXEL, Baltimore, MD, 3 PAREXEL, Berlin, Germany.
K. Francke: None. E. Neuhoff: None. W. Heber: None. J. Lambert:
None. M. Grossmann: None.
BACKGROUND: Experimental human pain models are widely used
to explore nociceptive mechanisms and to study the efficacy of novel
analgesic drugs. We previously used topical capsaicin cream to induce
pain, neuronal sensitization and neurogenic flare. However, the sensitivity
of the method was limited mainly due to inconsistent dermal absorption.
This study investigated the test-retest correlation and inter subject
variability of sensitization after intradermal capsaicin injection.
METHODS: In a 2-way crossover design, 28 healthy male volunteers
received intradermal injections of 90 μg Capsaicin (GMP grade;
30 μl, 0.3% solution in 7.5% Tween 80) to the volar forearm. The acute
pain, mechanical allodynia, pinprick hyperalgesia and neurogenic flare
reaction were assessed at several timepoints up to 60 min post injection.
The experiment was repeated 5 days later in exactly the same fashion.
RESULTS: Subjects perceived pain and developed neuronal sensitization
and neurogenic flare following capsaicin injection. Mean
values at 15 min post and correlation coefficients of test/retest were:
pain (NRS 11) 4.6±0.3, r= 0.81; mechanical allodynia 13.1±2.3 cm^2,
r= 0.82; pinprick hyperalgesia 18.1±2.4 cm^2, r= 0.73; flare 37.8±3.3
cm^2, r= 0.63.
CONCLUSION: Intradermal capsaicin injection is a suitable pain
model that can be utilized in early clinical drug development. The sensory
endpoints acute pain, allodynia and hyperalgesia showed acceptable
test-retest repeatability, but less correlation for neurogenic flare.
In general there was a trend towards lower responses in the second test
session. Intersubject comparisons showed considerable differences
in the extent of the induced sensory components, with some subjects
developing only small areas of hyperalgesia. This makes distinction
between primary and secondary sensitization difficult and limits the
dynamic range of the endpoint. Pre-screening is therefore recommended
to identify sensitive responders.
PI-77
PROPOFOL PHARMACOKINETICS IN CHILDREN IN EGYP-
TIEN POPULATION. A. A. Guemei, 1 R. S. Saleh, 2 A. M. El-Attar, 3
O. T. Fahmy 4 ; 1 Faculty of Medicine at King Fahad Medical City,
Riyadh, Saudi Arabia, 2 Faculty of Medicine, Alexandria University,
Alexandria, Egypt, 3 Faculty of Medicine, Alexandria University,
Alexandria, Egypt, 4 Faculty of Pharmacy, Alexandria University, Alexandria,
Egypt. A.A. Guemei: None. R.S. Saleh: None. A.M. El-Attar:
None. O.T. Fahmy: None.
BACKGROUND: Propofol has gained popularity as an agent for
both induction and maintenance of anesthesia for adults and children.
This is primarily because of its rapid onset, short duration of action and
minimal side effects. Pharmacokinetics of children is different from
adults. There had been a lack of pharmacokinetic studies in Egyptian
children less than 3 years of age.
METHODS: Forty eight pediatric patients (2-24 months) were randomly
assigned into 4 groups, each group had 12 patients. They were
scheduled to undergo superficial body surgery of 1 hour expected duration.
Venous blood samples were collected and analyzed using high
performance liquid chromatography (HPLC). Non linear mixed effects
modeling (NONMEN) software program was used to analyze the pharmacokinetic
data.
RESULTS: The pharmacokinetic of propofol in pediatric patients
followed a two compartment model with systemic clearance (Cl) 29.77
± 9.46 ml kg -1 min -1 , central volume of distribution (Vc) 0.62 ±0.24
kg -1 , and volume at steady state (Vss) 1.67 ± 0.26 kg -1 . The half life
(HL) was 0.24 ± 0.02h.
CONCLUSION: It was found that the children of this age have a larger
volume of distribution and a higher clearance of propofol than adults.
Therefore, the induction and maintenance doses should be increased in this
young age group using population based pharmacokinetic parameters.
PI-78
POPULATION MODELING OF THE PHARMACOKINETICS
AND PHARMACODYNAMICS OF PONESIMOD, A SELECTIVE
S1P1 RECEPTOR AGONIST. A. Krause, P. Brossard, D. D’Ambrosio,
J. Dingemanse; Actelion Pharmaceuticals, Allschwil, Switzerland.
A. Krause: 1. This research was sponsored by; Company/Drug;
Actelion Pharmaceuticals Ltd. 2. I am a paid consultant/employee
s36 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
for; Company/Drug; Actelion Pharmaceuticals Ltd. 6. I will be
discussing the following product, which is not labeled for the use
under discussion, or the product is still investigational; Company/
Drug; ponesimod. P. Brossard: 1. This research was sponsored
by; Company/ Drug; Actelion Pharmaceuticals Ltd. 2. I am a paid
consultant/employee for; Company/Drug; Actelion Pharmaceuticals
Ltd. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; ponesimod. D. D’Ambrosio: 1. This
research was sponsored by; Company/Drug; Actelion Pharmaceuticals
Ltd. 2. I am a paid consultant/employee for; Company/Drug;
Actelion Pharmaceuticals Ltd. 6. I will be discussing the following
product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; ponesimod. J.
Dingemanse: 1. This research was sponsored by; Company/Drug;
Actelion Pharmaceuticals Ltd. 2. I am a paid consultant/employee
for; Company/Drug; Actelion Pharmaceuticals Ltd. 6. I will be discussing
the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
ponesimod.
BACKGROUND: Sphingosine 1-phosphate (S1P) and the S1P
receptors play a central role in lymphocyte trafficking. The objective of
the pharmacokinetic (PK) and pharmacodynamic (PD) modeling was
to establish a quantitative framework for exposure-response relationships
aiding in dose selection to achieve therapeutic target ranges in
total lymphocyte count for ponesimod, a selective oral S1P 1 receptor
agonist.
METHODS: A nonlinear mixed effects model characterizes the PK
of ponesimod. The data originates from five phase I and one phase II
study and includes more than 200 individuals on starting doses from
1 to 75 mg and different up-titration regimens and 43 placebo subjects.
The PD model characterizes the effect on the total lymphocyte count,
the primary PD parameter for ponesimod.
RESULTS: The PK of ponesimod are characterized by a two compartment
model with absorption lag time and sequential zero/first order
absorption. Body weight was identified as a significant covariate on
volumes of distribution and drug clearance. The rate of appearance of
peripheral blood lymphocytes follows a circadian pattern. The ponesimod
concentration in the central compartment alters the rate of appearance
of the lymphocytes, described by an indirect effect E max model.
The PK and PD of ponesimod are characterized well by the integrated
model. The apparent volumes of distribution were identified as 36 and
219 L, respectively, the clearance as 6.5 L/h, and the absorption lag
time as 0.45 h. The maximum rate inhibition was estimated as 70%
with an IC 50 of 44 ng/mL. The PD effect reached a plateau at 80 percent
reduction in total lymphocyte count. Extrapolation to higher doses
accurately predicted the results of a subsequent study exploring doses
up to and including 100 mg.
CONCLUSION: The quantitative characterization of the PK and
PD of ponesimod has been achieved and formed the basis for dose
selection in patient trials. The model was able to predict the effect of
doses higher than observed so far.
PI-79
MODEL-BASED META-ANALYSIS (MBMA) OF TOTAL
MOTOR SCORE, CHOREA SCORE, AND TOTAL FUNCTIONAL
CAPACITY FOR PATIENTS WITH HUNTINGTON’S DISEASE
(HD). Y. Jin, S. Ahadieh, E. Pickering, R. Evans, J. Liu; Pfizer Inc,
Groton, CT. Y. Jin: None. S. Ahadieh: None. E. Pickering: None.
R. Evans: None. J. Liu: None.
BACKGROUND: No curative therapy is available for HD. Some
agents evaluated clinically seem to be effective in HD symptoms. We
aimed to evaluate natural disease progression, longitudinal placebo and
treatment effects on total motor score (TMS), total functional capacity
(TFC), and chorea score (CS) measures in HD patients.
METHODS: All randomized, double blinded, placebo-controlled
clinical trials conducted in HD patients were searched within
aBsTraCTs
MEDLINE, EMBASE, BIOSIS, and DERWENT. Fourteen, 11, and
10 studies representing 1821, 1521, and 840 subjects measuring TMS,
TFC, and CS, respectively, were available. The analyses were based
on study level data weighted by sample size. Placebo and treatment
effects were best modeled as Fig1.
RESULTS: TMS: Maximal placebo and treatment effects were
estimated to be the same -5.3 units (95%CI: -7.7 to -3.0), occurring
around 2.3 months. Natural disease progression rate was estimated
to be 6 units/yr (95%CI: 5.6 to 6.4). CS: Maximal placebo and treatment
effects were -0.49 units (95%CI: -0.95 to -0.03 ) and -0.88 units
(95%CI:-1.71 to -0.05), respectively, occurring around 1.25 months.
TFC: Neither placebo nor treatment effect identified. Natural disease
progression measured by TFC was -0.8 points/yr.
CONCLUSION: The analysis estimated natural disease progression,
placebo, and treatment effects on TMS, TFC, and CS for HD
patients. This could be used for supporting future study designs,
especially endpoint selection, study duration, and sample size
calculation.
TMSTreatment = (Pmax + η1 )(1 – e –(Kp +Kd +η2 )t ) + θ × ( ) Progression θ Age W
× t + × ε
49 N
CSTreatment = (Pmax + Dmax + η1 )(1 – e –Kp × t W
) + × ε
N
TFCPlacebol Treatment = θ ×e Progression η W
1 × t + × ε
N
P max and D max : maximum placebo and additional treatment effect respectively;
K p and K d : half life of reaching maximum effect;
Θ progression : the natural disease progression rate;
W: Standard deviation of each endpoint measure;
N: Sample size of each study;
η 1 and η 2 : between study variability;
ε: the residual error
Figure 1. Models describing placebo and treatment effect measured by TMS, CS, and TFC
PI-80
IMPORTANCE OF PK VARIABILITY ON DOSE SELECTION
FOR COMPOUNDS WITH POTENTIAL INVERTED U SHAPE
DOSE RESPONSE. Y. Jin, 1 J. Liu, 1 D. Nichols 2 ; 1 Pfizer Inc, Groton,
CT, 2 Pfizer Inc, Sandwich, United Kingdom. Y. Jin: None. J. Liu:
None. D. Nichols: None.
BACKGROUND: Potential inverted U shape dose response is
a consistent concern in CNS drug development, especially for dose
selection in clinical trials. The analysis aimed to evaluate the importance
of PK and PD variability on the dose selection for Phase 2 a like
trials by trial simulation methodology.
METHODS: Various inverted U shape dose response curves were
simulated using Gaussian function. Scenario I (narrow dose response):
True PD effect of 2, 6, and 2 at doses 20, 30, and 40 mg BID, respectively.
Scenario II (wider dose response): True PD effect of 2, 6, and 2 at
10, 30, and 50 mg BID, respectively. Scenario III (smaller effect): True
PD effect of 2, 4, and 2 at doses 20, 30, and 40 mg BID, respectively.
Sample size for each dose level was n=100 virtual subjects. Impact of
various PK variability (CV 20-80%) and PD effect size (Δ/SD: 200%,
100%, 50%) on trial results were evaluated. Predictive intervals (PI)
were derived with 1000 trial simulations.
RESULTS: Dose response identification in a Phase 2a like trials
were highly sensitive to PK variability vs. PD effect size (Δ/SD). Dose
response is only likely to be identified if PK variability

aBsTraCTs nature publishing group
CONCLUSION: Trial results are highly sensitive to PK variability
for compounds with potential inverted U shape response, hence it is
challenging to develop a drug with such attributes.
Response
0 1 2 3 4 5 6
Response
0 1 2 3 4 5 6
PK_CV=20%,∆/SD=200%
True dose response
Trial Result(90%PI)
10 20 30 40
Dose (BID mg)
PK_CV=80%, ∆/SD=200%
True dose response
Trial Result (90%PI)
10 20 30 40
Dose (BID mg)
Response
0 1 2 3 4 5 6
Response
0 1 2 3 4 5 6
PK_CV=20%,∆/SD=100%
10 20 30 40
Dose (BID mg)
PK_CV=80%,∆/SD=100%
10 20 30 40
Dose (BID mg)
Response
0 1 2 3 4 5 6
Response
0 1 2 3 4 5 6
PK_CV=20%, ∆/SD=50%
10 20 30 40
Dose (BID mg)
PK_CV=80%,∆/SD=50%
10 20 30 40
Dose (BID mg)
PI-81
CHARACTERIZATION OF GUINEA PIG MDR1/P-GP FUNC-
TION. I. Hasibu, D. Patoine, S. Pilote, B. Drolet, C. Simard; Institut
Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec,
QC, Canada. I. Hasibu: None. D. Patoine: None. S. Pilote: None.
B. Drolet: None. C. Simard: None.
INTRODUCTION: We have previously shown that guinea pigs
express MDR1/P-gp in small intestine. However, its function, as an
efflux pump involved in drug transport, has not been characterized.
The aim of this study was then to characterize MDR1 function and to
determine its distribution in different tissues.
METHODS: Molecular biology techniques (RNA extraction,
RACE-PCR, RT-PCR and Western blot) were used. Western blot and
RT-PCR analyses were performed using liver, small intestine, lung,
kidney, atrium, ventricle, cerebellum, brain and adrenal gland protein
extracts. Then, guinea pig MDR1 gene was cloned in pCI-neo vector
and transfected in HEK293 cells. The functional transport studies were
performed with the calcein assay (P-gp substrate) and using verapamil
as a P-gp inhibitor. The degree of inhibition of P-gp activity was quantified
by measuring the increase in intracellular calcein fluorescence.
RESULTS: RACE-PCR analyses showed a 1279 amino acid
sequence which is 85, 78, 81 and 78% homologous to human, mouse and
rat MDR1a and MDR1b, respectively. Western blot studies showed a 170
kDa band, highly suggestive of MDR1/P-gp. MDR1 mRNA was found in
liver, small intestine, atrium, ventricle, brain and adrenal gland. MDR1/
P-gp protein was found in liver, small intestine, atrium, ventricle, cerebellum,
brain and adrenal gland. Calcein assay confirmed the MDR1/P-gp
activity (84,76 ± 3,61 and 61,72 ± 5,29 FU for pCI-neo and guinea pig-
MDR1 transfected in HEK293 cells respectively, p=0,0034). Moreover, a
significant inhibition of guinea-pig/MDR1 transport activity was shown
when using verapamil (61,72 ± 5,29 and 91,13 ± 2,34 FU, p=0,0009).
CONCLUSION: These results suggest that guinea pigs express an
active MDR1/P-gp which was detected in almost the same tissues as
in humans. Considering the significance of this protein in drug transport,
this is reinforcing the pertinence of using the guinea pig model for
studying drug metabolism in a more “clinically relevant” context.
PI-82
CHARACTERIZATION OF GUINEA PIG CYP2C FUNCTION. I.
Hasibu, S. Pilote, D. Patoine, B. Drolet, C. Simard; Institut Universitaire
de Cardiologie et de Pneumologie de Quebec, Quebec, QC, Canada.
I. Hasibu: None. S. Pilote: None. D. Patoine: None. B. Drolet:
None. C. Simard: None.
BACKGROUND: The guinea pig expresses drug-metabolizing
enzymes such as CYP1A, CYP2B, CYP2D and CYP3A subfamilies. We
previously showed that this animal also expresses CYP2C and CYP2E
subfamilies. However, guinea pig CYP2C function has not been characterized.
The aim of our study was to characterize the guinea pig CYP2C
functional activity in order to use this animal for drug metabolism studies.
METHODS: Molecular biology techniques (RNA extraction,
RACE-PCR and Western blot) were used. The function was studied
with ex vivo standard incubations using hepatic microsomes from
guinea pig. A CYP2C9 probe drug (tolbutamide) was used. Inhibition
studies were performed with CYP2C9 inhibitors (tienilic acid and fluconazole)
and a CYP3A4 inhibitor (ketoconazole). Tolbutamide and
its metabolite concentrations were analyzed by HPLC.
RESULTS: RACE PCR allowed us to obtain a 1473 bp sequence
which is 80, 82, 81% homologous to human CYP2C8, CYP2C9 and
CYP2C19 cDNA respectively. Western blot allowed us to identify
a 55 kDa band, highly suggesting CYP2C signature. Incubations of
guinea pig hepatic microsomes revealed the formation of tolbutamide
specific CYP2C metabolite and showed a K m and a V max of 387 μM
and 195 pmol/min/mg proteins respectively. Inhibition assays revealed
that p-tolbutamide hydroxylase activity is inhibited by tienilic acid (a
mechanism-based inhibitor of CYP2C9), but not by fluconazole and
ketoconazole, specific inhibitors of CYP2C9, CYP3A4 respectively.
CONCLUSION: These results suggest that guinea pigs express
an active CYP2C subfamily, which is quite different from the human
CYP2C subfamily. However, when added to the confirmed expression of
CYP1A, CYP2B, CYP2D, CYP2E and CYP3A subfamilies and considering
the number of drugs metabolized by these hepatic subfamilies, this
is reinforcing the pertinence of using the guinea pig model for studying
drug metabolism in a more “clinically relevant” context.
PI-83
A NEWLY DEVELOPED PEDIATRIC FORMULATION OF REVA-
TIO FOR PEDIATRIC PULMONARY ARTERIAL HYPERTENSION
PATIENTS IS BIOEQUIVALENT TO THE 1X20 MG REVATIO COM-
MERCIAL TABLET AND TO THE 2X10 MG SILDENAFIL CITRATE
CLINICAL TRIAL TABLETS IN HEALTHY ADULT VOLUNTEERS.
X. Gao, L. Robert, M. O’Gorman, J. Cook; Pfizer, Inc, Groton, CT.
X. Gao: 1. This research was sponsored by; Company/Drug; Pfizer,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer,
Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer, Inc.
6. I will be discussing the following product, which is not labeled for the
use under discussion, or the product is still investigational; Company/
Drug; Revatio formulation for pediatric use. L. Robert: 1. This research
was sponsored by; Company/Drug; Pfizer, Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer, Inc. 5. I am a significant
stockholder for; Company/ Drug; Pfizer, Inc. 6. I will be discussing the
following product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Revatio formulation
for pediatric use, which is not approved in US yet, but it is pending
on approval from EU. M. O’Gorman: 1. This research was sponsored
by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee
for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder for;
Company/Drug; Pfizer Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; the pediatric formulation of Revatio
was not approved in US yet, but it was pending approval in Europe.
J. Cook: 1. This research was sponsored by; Company/ Drug; Pfizer
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer Inc.
5. I am a significant stockholder for; Company/ Drug; Pfizer Inc. 6. I will
be discussing the following product, which is not labeled for the use
under discussion, or the product is still investigational; Company/Drug;
Revatio pediatric formulation which has not approved in US yet.
BACKGROUND: Revatio is approved for pediatric pulmonary
arterial hypertension (PAH) patients in EU based on the results of a
large multicentre RCT (STARTS-1). Accordingly, a new pediatric
formulation, 10 mg/mL sildenafil citrate powder for oral suspension
(POS) was developed for the treatment of pediatric PAH patients.
s38 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
METHODS: A pivotal randomized, open-label, 3-way crossover
study was conducted to demonstrate bioequivalence of the 20 mg (2 ml
of 10 mg/ml) POS relative to the Revatio 1x 20 mg commercial tablet
and the sildenafil citrate 2x10 mg clinical trial tablet in healthy adult
volunteers under fasting conditions. Forty-two (42) subjects received
three sildenafil treatments in a crossover manner as indicated above.
Plasma samples were collected at the predefined series times and analyzed
for sildenafil concentrations. Sildenafil PK parameters (C max ,
AUC last , and AUC inf ) were evaluated for bioequivalence of 20 mg POS
relative to Revatio 1x 20 mg tablet and 2x 10 mg tablets.
RESULTS: The statistical analyses demonstrated that 20 mg sildenafil
POS formulation is bioequivalent to 1x 20 mg Revatio tablet and
2x10 mg sildenafil tablets, as the 90% confidence interval (CI) for
the adjusted geometric means of C max , AUC last , and AUC inf , were all
within 80% to 125%, the bioequivalence criteria specified by FDA and
EMEA. In addition, these three formulations were well tolerated by the
healthy volunteers in this study.
CONCLUSION: 20 mg (10 mg/mL) sildenafil citrate POS, a newly
developed pediatric formulation, is bioequivalent to 1x 20 mg Revatio
tablet and 2x10 mg sildenafil tablets.
PI-84
A PHASE 1 STUDY TO ASSESS THE EFFECT OF LU AA21004
ON THE STEADY-STATE PHARMACOKINETICS OF LITHIUM
IN HEALTHY MALE SUBJECTS. G. Chen, R. Lee, Z. Zhao, M. Serenko;
Takeda Global Research and Development Center, Deerfield, IL.
G. Chen: 1. This research was sponsored by; Company/Drug; Takeda
Pharmaceutical Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee
for; Company/Drug; Takeda Global Research and
Development Center. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; Lu AA21004. R. Lee: 1. This
research was sponsored by; Company/Drug; Takeda Pharmaceutical
Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee
for; Company/Drug; Takeda Global Research and Development
Center. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Lu AA21004. Z. Zhao: 1. This research was
sponsored by; Company/Drug; Takeda Pharmaceutical Company, Ltd,
H. Lundbeck A/S. 2. I am a paid consultant/employee for; Company/
Drug; Takeda Global Research and Development Center. 6. I will
be discussing the following product, which is not labeled for the use
under discussion, or the product is still investigational; Company/
Drug; Lu AA21004. M. Serenko: 1. This research was sponsored by;
Company/Drug; Takeda Pharmaceutical Company, Ltd, H. Lundbeck
A/S. 2. I am a paid consultant/employee for; Company/Drug; Takeda
Global Research and Development Center. 6. I will be discussing the
following product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; Lu AA21004.
BACKGROUND: Lu AA21004 is a multimodal antidepressant,
currently in clinical development for the treatment of major depressive
disorder. Lithium has a narrow therapeutic index and is often
combined with antidepressants for treatment of refractory depression
and bipolar disorders. The pharmacokinetics (PK), safety and
tolerability of lithium when coadministered with Lu AA21004 are of
clinical interest.
METHODS: In this single-blind, multiple-dose, single sequence
study, 18 healthy men (mean age 33.2 years) received lithium carbonate
450 mg extended release (ER) tablet twice daily (BID) and placebo
capsule once daily (QD) on Days 1-14, followed by lithium carbonate
450 mg ER tablet BID and Lu AA21004 10 mg over-encapsulated
tablet QD on Days 15-28. Blood and urine samples were obtained
up to 12 hours postdose on Days 14 and 28 for the determination of
lithium concentrations. Lithium PK parameters were estimated using
noncompartmental methods. Statistical analysis to evaluate the effect
of multiple doses of Lu AA21004 on the steady state pharmacokinetics
of lithium was performed using ANOVA. Adverse events (AEs) were
monitored throughout the study.
aBsTraCTs
RESULTS: A total of 16 subjects were included in the analysis.
The 90% confidence intervals for the least square mean ratios of Lu
AA21004 and lithium to placebo and lithium for AUC (0-12) , C max , and
C min for lithium ranged from 91.0% to 110.7% (within the 80% to
125% no-effect boundary). Median T max values for Day 14 and Day 28
were identical. Urine PK parameters (A e [0-12], CLr, and Fe) of lithium
on Day 14 and Day 28 were generally similar. Nasal congestion was
the only AE reported more frequently with Lu AA21004 and lithium
treatment (31.3%) than with placebo and lithium treatment (5.6%). All
treatment emergent AEs were mild in intensity.
CONCLUSION: Multiple doses of Lu AA21004 10 mg did not
affect the steady state pharmacokinetics of lithium. Coadministration
of Lu AA21004 10 mg QD with lithium 450 mg ER BID for 14 days
was generally well tolerated.
PI-85
A POPULATION ANALYSIS OF UNBOUND MYCOPHENOLIC
ACID PHARMACOKINETICS AND PHARMACOGENETICS IN
ADULT ALLOGENEIC HEMATOPOIETIC CELL TRANSPLAN-
TATION. A. Frymoyer, 1 D. Verotta, 1 P. A. Jacobson, 2 J. Long-Boyle 1 ;
1 University of California, San Francisco, San Francisco, CA, 2 University
of Minnesota, Minneapolis, MN. A. Frymoyer: None. D. Verotta:
None. P.A. Jacobson: None. J. Long-Boyle: None.
BACKGROUND: Unbound mycophenolic acid (MPA u ) pharmacokinetics
(PK) in adult allogeneic hematopoietic cell transplantation
(alloHCT) recipients displays large inter- and intrapatient variability,
and lower exposure is associated with higher rates of acute graft vs
host disease (aGVHD). The aim of this study was to evaluate patientspecific
covariates, both genetic and non-genetic, as contributors to the
variability of unbound MPA exposure and clinical outcomes in adult
alloHCT recipients.
METHODS: Intensive MPA u PK data obtained in 132 adult
alloHCT recipients (38% female; mean [range] age 52 yrs [19-69
yrs]) from three previously completed clinical studies were used. A
population-based PK model of MPA u was developed using nonlinear
mixed-effects modeling (NONMEM). Clinical characteristics,
concomitant medications and genetic polymorphisms (UGT1A8,
UGT1A9, UGT2B7, and MRP2) were evaluated for their impact on
MPA u PK. The relationship between daily MPA u AUC (AUC24) and
aGVHD (grade II-IV and III-IV) was examined using a competingrisks
survival regression analysis.
RESULTS: MPA u concentration-time data was well described by a
two-compartment model with first order absorption and linear elimination.
Creatinine clearance was a small but significant predictor of MPA u
CL. No other covariates tested were found to influence MPA u PK. Interpatient
variability in CL, V central , and k a was 37%, 38%, and 73%, respectively.
After oral dosing, bioavailability was low (0.56) and highly variable
(CV 46%). Residual variability was 42%. The risk of aGVHD grade II-IV
decreased 16% for every 200 ng*h/ml increase in AUC24 (p

aBsTraCTs nature publishing group
BACKGROUND: Green tea contains large amounts of catechins
which have recently been reported to affect the activity of organic
anion transporting polypeptides as well as P-glycoprotein in vitro. This
study evaluated the effect of green tea on the pharmacokinetics and
pharmacodynamics of nadolol, a hydrophilic and non-metabolized
beta adrenoceptor antagonist in healthy adults.
METHODS: An open-label, two-period crossover study was conducted
in 12 healthy volunteers. After chronic consumption of green
tea or water (700 mL/day) for 14 days, subjects received a single oral
dose of 30 mg nadolol with 350 mL of green tea or water. The total
content of catechins in green tea was 0.9 mg/mL. Blood sampling
and measurements of blood pressure and heart rate were performed
over 48 hours after nadolol administration. Plasma concentrations of
nadolol were determined using HPLC with fluorescence detection.
Pharmacokinetic parameters were estimated by non-compartmental
analysis.
RESULTS: Median T max of nadolol in water and green tea phases
were 3.0 and 1.5 hours, respectively. The geometric mean ratio for
(nadolol + green tea/nadolol + water) and 90% confidence intervals for
nadolol AUC 0-∞ and C max were 0.22 (0.08-0.36) and 0.20 (0.06-0.34),
respectively. The elimination half-life of nadolol in green tea was prolonged
by 2.2 times compared with water. Nadolol reduced systolic
blood pressure by 12% from baseline value in water phase, however no
such reduction was observed in green tea phase.
CONCLUSION: The chronic consumption of green tea may significantly
decrease the plasma concentration of nadolol and reduce its
pharmacodynamic response.
PI-87
A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY
OF PEG-G-CSF IN CANCER PATIENTS WITH CHEMOTHERAPY-
INDUCED NEUTROPENIA. Z. Li, 1 W. Jin, 2 H. Mei, 3 W. Qi, 4 L. Hua 5 ;
1 Institute of Clinical Pharmacology ,West China Hospital of ShiChuan
University, Chengdu, China, 2 Oncology Center ,West China Hospital
of ShiChuan University, Chengdu, China, 3 Oncology Center,West
China Hospital of ShiChuan University, Chengdu, China, 4 Oncology
Department, ShiChuan Province Hospital, Chengdu, China, 5 Chongqin
Biomedicine Limited Company, Chongqin, China. Z. Li: None. W.
Jin: None. H. Mei: None. W. Qi: None. L. Hua: None.
BACKGROUND: The newly developed generic PEG-G-CSF, a
long-acting granulocyte colony-stimulating factor, was established in
China. The aim of this study was to investigate the safety, pharmacokinetic
and pharmacodynamic profiles of PEG-G-CSF in cancer patients
with chemotherapy-induced neutropenia.
METHODS: This open-label, randomized-sequence, 2-way
crossover study was conducted at two hospitals in China. Ten Chinese
cancer patients (eight patients with nonsmall-cell lung cancer
and two patients with lymphoma) who had experienced severe neutropenia
were enrolled. Patients received the same chemotherapy
regimen in each cycle. Patients were randomly assigned at a 1:1 ratio
to receive a single subcutaneous dose of 60 ug/kg PEG-G-CSF or a
daily subcutaneous dose of 5 μg/kg filgrastim at the 48 hours after
chemotherapy ended in the first chemotherapy cycle and administration
of the alternate formulation in the second cycle. Pharmacokinetic,
pharmacodynamic and safety analyses were performed. Blood
samples for PEG-G-CSF concentration measurement were collected
before PEG-G-CSF administration and from 1 to 432 hours after the
injection of PEG-G-CSF.
RESULTS: PEG-G-CSF and filgrastim were similar for all efficacy
and safety end points. The main pharmacokinetic parameters of PEG-
G-CSF are as follow: T max : 21.0±11.0 h, C max : 138.4±31.3 μg/L, t 1/2z :
64.2±11.0h, CL: 0.006±0.002 L/h/kg, AUC (0~t) : 11105±2643 μg/L/h.
Serum concentrations of PEG-G-CSF began to decrease after day 5 at
the end of chemotherapy and returned to baseline levels on day 15.
CONCLUSION: The tolerance, pharmacokinetic and pharmacodynamic
characteristics of PEG-G-CSF supports a single dose of 60 ug/
kg subcutaneous injection once per treatment cycle for prevention of
severe neutropenia.
PI-88
PHARMACOKINETIC AND PHARMACODYNAMIC EVALU-
ATION OF A NOVEL K + -COMPETITIVE ACID PUMP ANTAGO-
NIST, YH4808, IN HEALTHY VOLUNTEERS. S. J. Yi, 1 S. Y. Nam, 2
H. M. Byun, 2 S. B. Jang, 2 H. Jeon, 1 S. E. Kim, 1 S. H. Yoon, 1 K. S. Lim, 1
J. Y. Cho, 1 S. G. Shin, 1 I. J. Jang, 1 K. S. Yu 1 ; 1 Seoul National University
College of Medicine and Hospital, Seoul, Korea, Republic of, 2 R&D,
Yuhan Corporation, Seoul, Republic of Korea. S.J. Yi: 1. This research
was sponsored by; Company/Drug; Yuhan Co. Ltd. (Seoul, Korea).
S.Y. Nam: 1. This research was sponsored by; Company/Drug;
Yuhan Co. Ltd. (Seoul, Korea). 2. I am a paid consultant/employee for;
Company/Drug; Yuhan Co. Ltd. (Seoul, Korea). H.M. Byun: 1. This
research was sponsored by; Company/Drug; Yuhan Co. Ltd. (Seoul,
Korea). 2. I am a paid consultant/employee for; Company/Drug; Yuhan
Co. Ltd. (Seoul, Korea). S.B. Jang: 1. This research was sponsored by;
Company/Drug; Yuhan Co. Ltd. (Seoul, Korea). 2. I am a paid consultant/employee
for; Company/Drug; Yuhan Co. Ltd. (Seoul, Korea).
H. Jeon: 1. This research was sponsored by; Company/Drug; Yuhan
Co. Ltd. (Seoul, Korea). S.E. Kim: 1. This research was sponsored by;
Company/Drug; Yuhan Co. Ltd. (Seoul, Korea). S.H. Yoon: 1. This
research was sponsored by; Company/Drug; Yuhan Co. Ltd. (Seoul,
Korea). K.S. Lim: 1. This research was sponsored by; Company/Drug;
Yuhan Co. Ltd. (Seoul, Korea). J.Y. Cho: 1. This research was sponsored
by; Company/Drug; Yuhan Co. Ltd. (Seoul, Korea). S.G. Shin: 1. This
research was sponsored by; Company/Drug; Yuhan Co. Ltd. (Seoul,
Korea). I.J. Jang: 1. This research was sponsored by; Company/Drug;
Yuhan Co. Ltd. (Seoul, Korea). K.S. Yu: 1. This research was sponsored
by; Company/Drug; Yuhan Co. Ltd. (Seoul, Korea).
BACKGROUND: YH4808, a novel K + -competitive acid pump
antagonist, is under clinical development for the treatment of gastroesophageal
reflux disease. The aim of this study was to evaluate the
pharmacokinetics (PK), pharmacodynamics and tolerability following
single and multiple oral doses of YH4808.
METHODS: A dose-block randomized, double-blind, placebo- and
active comparator-controlled, single/multiple ascending dose study was
conducted in healthy subjects (single dose of 30-800mg; multiple dose
of 100, 200, 400mg per day for 7 days). In each dose group, 12 subjects
were assigned to YH4808, placebo or esomeprazole (E) 40mg QD in a
ratio of 8:2:2. A 24-h gastric pH was measured before and after single or
multiple dosing. PK was analyzed using noncompartmental methods.
RESULTS: A total of 124 subjects completed the study with neither
serious nor dose-dependent adverse events. Plasma concentrations
of YH4808 reached peak levels within 1.0h, and then declined
bi-exponentially with an effective half-life of 2.3-5.4h. The AUC and
C max increased dose-proportionally and accumulation after multiple
dosing was minimal. After YH4808 administration, mean pH and proportion
of pH>4 holding time increased dose-dependently compared
to baseline or placebo, and YH4808 ≥200 mg/day maintained gastric
pH higher than E (Mean pH: 5.1-5.4 vs 4.0 after single dose, 5.0-5.2
vs 4.3 at steady state; proportion of pH>4 holding time: 67.9-76.3%
vs 51.5% after single dose, 71.5-78.5% vs 58.3% at steady state). In
all doses of YH4808, the area under pH-time curve from 0 to 2 h was
significantly greater than that of E (Mean AUEC 0-2h (pH*min): 367.8-
530.3 vs 276.7 after single dose, 524.9-734.5 vs 387.7 at steady state),
indicating that YH4808 increases gastric pH more rapidly than E.
CONCLUSION: YH4808 is safe and well tolerated and exhibits
dose-proportional PK over a dose range of 30-800mg. It was more
sustained, greater and faster gastric acid inhibition than E at doses of
≥200 mg/day.
PI-89
EXPOSURE-RESPONSE MODELING OF LY2439821 (AN
ANTI-IL-17 MONOCLONAL ANTIBODY) IN PATIENTS WITH
MODERATE-TO-SEVERE PSORIASIS. C. Tang, 1 S. Choi, 1
J. Satterwhite, 2 G. Cameron, 2 S. Banerjee, 2 L. Tham 1 ; 1 Lilly-NUS
Centre for Clinical Pharmacology Pte Ltd, Singapore, Singapore,
2 Eli Lilly and Company, Indianapolis, IN. C. Tang: 1. This research
was sponsored by; Company/Drug; Eli Lilly and Company. 2. I am
s40 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt

nature publishing group
a paid consultant/employee for; Company/Drug; Eli Lilly and Company.
S. Choi: 1. This research was sponsored by; Company/Drug;
Eli Lilly and Company. 2. I am a paid consultant/employee for; Company/Drug;
Eli Lilly and Company. J. Satterwhite: 1. This research
was sponsored by; Company/Drug; Eli Lilly and Company. 2. I am
a paid consultant/employee for; Company/Drug; Eli Lilly and Company.
G. Cameron: 1. This research was sponsored by; Company/
Drug; Eli Lilly and Company. 2. I am a paid consultant/employee
for; Company/Drug; Eli Lilly and Company. S. Banerjee: 1. This
research was sponsored by; Company/Drug; Eli Lilly and Company.
2. I am a paid consultant/employee for; Company/Drug; Eli Lilly and
Company. L. Tham: 1. This research was sponsored by; Company/
Drug; Eli Lilly and Company. 2. I am a paid consultant/employee for;
Company/Drug; Eli Lilly and Company. 6. I will be discussing the
following product, which is not labeled for the use under discussion, or
the product is still investigational; Company/Drug; LY2439821.
BACKGROUND: LY2439821 is an anti-interleukin-17 monoclonal
antibody in development for treatment of psoriasis. The objective
was to describe the exposure-response relationship of LY2439821
and PASI (Psoriasis Area and Severity Index) scores in a Phase 2b
dose-finding study.
METHODS: A semi-mechanistic indirect response model was
used to describe dose-concentration-clinical efficacy relationships
for psoriasis following subcutaneous administration of LY2439821.
LY2439821 and placebo were assumed to exhibit an inhibitory effect
on formation of psoriatic lesions represented by PASI score. The PASI
75 and 90 (75% and 90% reductions in PASI score, respectively)
responses for each dose were subsequently determined through 200
simulations of model-predicted PASI scores.
RESULTS: PK/PD modeling was conducted via NONMEM VII on
651 LY2439821 PK concentrations and 1445 PASI scores from 142
patients with moderate-to-severe psoriasis. Patients received placebo
and doses ranging from 10 to 150 mg LY2439821 on weeks 0, 2, 4,
8, 12 and 16. A sequential modeling approach using empirical Bayesian
estimates of individual PK parameters from a 2-compartment PK
model with first-order SC absorption and elimination rate constants
was applied. Population parameter estimates [95% CI] for maximum
placebo response, placebo effect half-life, maximum LY2439821
response, baseline PASI score, Hill’s coefficient and rate constant for
improvement of skin lesions were 13.2 [-0.709, 28.1] %, 10.8 [1.60,
21.4] days, 100% (fixed), 15.9 [15.3, 16.8] PASI units, 0.805 [0.724,
0.922], and 0.889 [0.760, 1.02] PASI units/day, respectively. At 10 mg,
exposures were close to concentration for half maximal effect.
CONCLUSION: The PK/PD model described exposure-response
relationship for LY2439821 in psoriasis patients well and modelpredicted
PASI 75 and PASI 90 response concurred with observed
response rates. This model was utilized to inform dose-selection for
Phase 3 development.
PI-90
EFFECT OF ACTIVATED CHARCOAL ON THE PHARMA-
COKINETICS OF APIXABAN IN HEALTHY SUBJECTS. X. Wang,
G. Tirucherai, N. Pannacciulli, J. Wang, A. Elsrougy, V. Teslenko,
M. Chang, D. Zhang, C. Frost; Bristol-Myers Squibb, Princeton,
NJ. X. Wang: 1. This research was sponsored by; Company/Drug;
Bristol-Myers Squibb. 2. I am a paid consultant/employee for; Company/Drug;
Bristol-Myers Squibb. G. Tirucherai: 1. This research
was sponsored by; Company/Drug; Bristol-Myers Squibb. 2. I am a
paid consultant/employee for; Company/Drug; Bristol-Myers Squibb.
N. Pannacciulli: 1. This research was sponsored by; Company/
Drug; Bristol-Myers Squibb. 2. I am a paid consultant/employee for;
Company/Drug; Bristol-Myers Squibb. J. Wang: 1. This research
was sponsored by; Company/Drug; Bristol-Myers Squibb. 2. I am
a paid consultant/employee for; Company/Drug; Bristol-Myers
Squibb. A. Elsrougy: 1. This research was sponsored by; Company/
Drug; Bristol-Myers Squibb. 2. I am a paid consultant/employee for;
Company/ Drug; Bristol-Myers Squibb. V. Teslenko: 1. This research
was sponsored by; Company/Drug; Bristol-Myers Squibb. 2. I am
aBsTraCTs
a paid consultant/employee for; Company/Drug; Bristol-Myers
Squibb. M. Chang: 1. This research was sponsored by; Company/
Drug; Bristol-Myers Squibb. 2. I am a paid consultant/employee for;
Company/ Drug; Bristol-Myers Squibb. D. Zhang: 1. This research
was sponsored by; Company/Drug; Bristol-Myers Squibb. 2. I am a
paid consultant/employee for; Company/Drug; Bristol-Myers Squibb.
C. Frost: 1. This research was sponsored by; Company/Drug; Bristol-
Myers Squibb. 2. I am a paid consultant/employee for; Company/
Drug; Bristol-Myers Squibb.
BACKGROUND: Apixaban is a novel, orally-active factor Xa
inhibitor approved in Europe for preventing venous thromboembolism
following knee or hip replacement surgery. Presently, there is no antidote
for apixaban overdose or accidental ingestion. Activated charcoal
is commonly used to manage overdose or accidental ingestion of medicines.
A study in beagle dogs showed up to 19% and 37% decrease in
apixaban exposure when charcoal (250 mg/kg) was administered 1 and
3 hours after a dose of apixaban 5 mg/kg, respectively. This study evaluated
the effect of charcoal on apixaban exposure in healthy subjects.
METHODS: This was an open-label, three-treatment, three-period,
randomized, crossover study of single dose apixaban (20 mg) administered
with or without charcoal suspension (50 g activated charcoal and
96 g sorbitol in 240 mL water) to 18 healthy subjects. Charcoal suspension
was administered at 2 hours or 6 hours postdose. Blood samples
were collected up to 72 hours post apixaban dose, with a 4-day washout
between each treatment. Pharmacokinetic parameters (C max , T max ,
AUC( 0-T ), and AUC( INF )) were derived from plasma concentration-time
data for apixaban. A general linear mixed effect model analysis was performed
to estimate the effect of charcoal on apixaban exposure.
RESULTS: Compared to apixaban alone, apixaban mean AUC( INF )
was decreased by 50% (ratio of LS means: 0.50; 90% CI: 0.46 - 0.55)
when charcoal was administered 2 hours postdose and by 26% (ratio of
LS means: 0.74; 90% CI: 0.67 - 0.81) when charcoal was administered
6 hours postdose. Mean C max and median T max were similar across all
3 treatments.
CONCLUSION: Administration of activated charcoal up to 6 hours
after apixaban administration significantly reduced apixaban exposure.
Activated charcoal may be useful to manage apixaban overdose or
accidental ingestion.
PI-91
A CLINICAL STUDY TO ASSESS EFFECT OF RIFAMPIN ON
THE PHARMACOKINETICS (PK) OF NERATINIB (HKI-272),
A PAN-ERBB RECEPTOR TYROSINE KINASE INHIBITOR,
WHEN ADMINISTERED CONCOMITANTLY IN HEALTHY
SUBJECTS. R. Abbas, B. Hug, C. Leister, D. Sonnichsen; Pfizer,
Collegeville, PA. R. Abbas: 2. I am a paid consultant/employee for;
Company/Drug; Pfizer. B. Hug: 2. I am a paid consultant/employee
for; Company/Drug; Pfizer. C. Leister: 2. I am a paid consultant/
employee for; Company/Drug; Pfizer. D. Sonnichsen: 2. I am a paid
consultant/employee for; Company/Drug; Pfizer.
BACKGROUND: Neratinib (NER) is a potent, low-molecularweight,
orally administered, irreversible pan-ErbB receptor tyrosine
kinase inhibitor that has demonstrated activity in patients with ErbB2+
breast cancer. In vitro data indicate that NER is mainly metabolized
by CYP3A4 and flavin-containing mono-oxygenases (FMOs), with
CYP3A4 forming M3, M6, and small amounts of M7, and FMOs forming
most of M7. The objective of this study was to assess the effect of
multiple doses of rifampin (potent CYP3A4 inducer, RIF) on the PK
and safety of a single dose of NER in healthy subjects.
METHODS: Subjects received NER 240 mg alone with breakfast
on day 1, RIF 600 mg alone (fasting) on days 8-13 and 15, and RIF
600 mg (fasting) followed by NER 240 mg with breakfast 1 hour later
on day 14. Blood samples were collected on days 1 and 14 before and
through 48 hours after NER administration. Plasma concentrations of
NER and metabolites (M3, M6, M7) were measured by LC/MS/MS.
PK analyses were performed using a noncompartmental method.
RESULTS: On-treatment adverse events (AEs) occurred in
13 (54%) subjects after administration of NER alone and 5 (22%)
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aBsTraCTs nature publishing group
subjects after coadministration of NER+RIF. The most common
on-treatment AEs were diarrhea (n=8 [33%], oropharyngeal pain
(6 [25%]), and seborrhoeic dermatitis (2 [8%]). There were no AErelated
discontinuations. As a result of rifampin’s induction effect, during
coadministration, NER C max and AUC substantially decreased to
24.1% and 12.7%, respectively, of values observed with NER alone;
correspondingly, NER metabolite C max was significantly increased by
about 2.3-fold for M3, 1.5-fold for M6, and 1.4-fold for M7 compared
with values after administration of NER alone.
CONCLUSION: The results indicate that NER, a substrate
of CYP3A4, is susceptible to interaction with potent CYP3A4
inducers.
PI-92
USE OF A PHARMACOKINETIC-PHARMACODYNAMIC
(PKPD) MODEL FRAMEWORK IN THE DESIGN OF A DOSING
REGIMEN FOCUSED ON RESPONSE. A. Grover, L. Z. Benet; University
of California, San Francisco, San Francisco, CA. A. Grover:
None. L.Z. Benet: None.
BACKGROUND: Grover and Benet (J Pharmacokinet Pharmacodyn
(2011)) argue that pharmacokinetic dosing interval predictors
will be more relevant for direct PKPD model drugs than they will be
for indirect PKPD model drugs. As the direct-indirect distinction is
actually a continuum, we sought to determine if a pattern in PKPD
model parameters (k e0 and k out for the indirect link (IDL) and indirect
response (IDR) models, respectively) can be discerned to be used as
additional guidance in determining a dosing regimen.
METHODS: The relevance of pharmacokinetic dosing interval predictors
was determined as the ratio of the longest recommended dosing
interval to the time plasma concentrations are over an efficacy EC 50 .
Using a number of case studies from the literature, we simulated the
time plasma concentrations are above the EC 50 during multiple dosing
steady state at the second to lowest approved dose and at the longest
recommended dosing interval.
RESULTS: The relationship between the ratio of the dosing interval
to time above EC 50 and k e0 or k out is approximately log-linear (r 2 =
0.750, p < 0.001, n = 15), and a k e0 or k out value greater than 2 hr -1 (e.g.
terbutaline, atropine, ranitidine) provides a dosing interval predicted
by the pharmacokinetics. A finding that k e0 or k out is below 0.5 hr -1
(e.g. terazosin, dexamethasone) indicates that pharmacokinetic dosing
interval predictors will not be clinically relevant. By combining efficacy
and toxicity PKPD models for a single drug (here, levodopa), we
show that this regression can be used to design a dosing regimen such
that efficacy falls along the regression and toxicities appear underdosed.
CONCLUSION: As a basic PKPD model should be derived early
in clinical trials, the log-linear regression can be used as a framework
within which to understand the relevance of pharmacokinetic dosing
interval predictors and as a guide for determining dosing regimens that
are considerate of efficacious and toxic response for both IDL and IDR
model drugs.
PI-93
ORAL MIDAZOLAM (MDZ) PARTIAL AREA-UNDER CURVE
(AUC) DOES NOT RELIABLY PREDICT CYTOCHROME P450
(CYP) 3A BASELINE ACTIVITY IN HEALTHY SUBJECTS. W.
Tai, 1 S. L. Gong, 1 S. M. Tsunoda, 1 H. E. Greenberg, 2 J. C. Gorski, 3
S. R. Penzak, 4 S. A. Stoch, 5 J. D. Ma 1 ; 1 UCSD, Skaggs School of
Pharmacy & Pharmaceutical Sciences, La Jolla, CA, 2 Department of
Pharmacology and Experimental Therapeutics, Thomas Jefferson University,
Philadelphia, PA, 3 Mylan Pharmaceuticals, Morgantown, WV,
4 Pharmacy Department, National Institutes of Health, Bethesda, MD,
5 Merck, Rahway, NJ. W. Tai: None. S.L. Gong: None. S.M. Tsunoda:
None. H.E. Greenberg: None. J.C. Gorski: None. S.R. Penzak:
None. S.A. Stoch: None. J.D. Ma: None.
BACKGROUND: MDZ clearance (CL) and AUC INF are used as
biomarkers to predict CYP3A activity. A recent study recommended
a MDZ partial AUC from 2 to 4 hr to predict MDZ metabolic CL. We
evaluated a partial AUC approach to predict MDZ CL and thus CYP3A
activity during baseline conditions.
METHODS: MDZ plasma concentrations from 116 healthy adults
were obtained from seven published studies. Observed CL, AUC, and
partial AUCs over several intervals were determined via noncompartmental
analysis. Subject data were randomly divided into a training
set (n=30) and a validation set (n=86). Linear regression analyses of
log-transformed partial AUCs were performed using the training set.
MDZ predicted CL was determined from the validation set. Backtransformed
predicted CL was compared to observed CL. Bias and
precision were evaluated by percent mean precision error (%MPE),
percent mean absolute error (%MAE), and percent root mean square
error (%RMSE).
RESULTS:
Model
equation
AUC 0-2 AUC 0-6 AUC 2-4
-0.33*
[log(AUC 0-2 )] +5.45
-0.43*
[log(AUC 0-6 )] +5.68
-0.44*
[log(AUC 2-4 )] +5.45
r2 0.26 0.40 0.47
Mean
predicted
CL
113.04 L/hr 114.29 L/hr 113.27 L/hr
Mean
observed
CL
115.34 L/hr 115.34 L/hr 115.34 L/hr
%MPE
(±5%)
-1.7 -0.7 -1.7
%MAE
(

nature publishing group
the validation set. Bias and precision were assessed via percent mean
prediction error (%MPE), percent mean absolute error (%MAE), and
percent root mean square error (%RMSE), with acceptable limits being
±5,

aBsTraCTs nature publishing group
PI-97
POPULATION PHARMACOKINETIC ANALYSIS OF RUX-
OLITINIB IN SUBJECTS WITH MYELOFIBROSIS. X. Chen, X.
Liu, S. Peng, W. V. Williams, V. Sandor, S. Yeleswaram; Incyte Corp.,
Wilmington, DE. X. Chen: None. X. Liu: None. S. Peng: None.
W.V. Williams: None. V. Sandor: None. S. Yeleswaram: None.
BACKGROUND: A population PK model was developed to characterize
the PK of ruxolitinib, a selective inhibitor of Janus kinase
(JAK) 1 and 2, and a Class 1 compound in the Biopharmaceutical Classification
System (BCS), in development for treatment of myeloproliferative
neoplasms.
METHODS: Data from a Phase 2 and a Phase 3 study were used as
the modeling dataset. Data from a second Phase 3 study was used for
validation. Demographics, disease state, clinical laboratory values and
concomitant medications were explored as predictors of PK variability.
Stepwise regression was used to include and eliminate covariates. The
visual predictive check (VPC) and external data validation was used to
assess the overall predictive performance of the final model.
RESULTS: The modeling dataset included 2187 concentrations
from 272 subjects. The external validation dataset contained 1067 concentrations
from 142 subjects. The PK of ruxolitinib was adequately
described by a 2-compartment disposition model with first-order
absorption and linear elimination. All model parameters were estimated
with good precision (≤ 20.3 %SEM and ≤ 43.7% SEM for fixed
and random effect parameters, respectively). Gender and body weight
were identified as covariates for CL and Vc/F, respectively. Apparent
oral clearance was 22.1 L/h and 17.7 L/h for a typical male and female
subject, respectively, with 39.1% unexplained inter-individual variability
(IIV). The typical V c /F for a subject with a median weight of 72.9
kg was estimated to be 58.6 L, with 28% unexplained IIV. The VPC
showed that 89.9% of the observed data fell within the 5th and 95th
percentiles of the simulated data. The model predictive performance
was validated by the external data.
CONCLUSION: Although gender and body weight were statistically
significant predictors of ruxolitinib PK, the geometric mean ratios
for both parameters fell within interval of .5 to 2 and were therefore not
clinically significant.
PI-98
POPULATION PK/PD ANALYSIS OF SPLEEN VOLUME IN
SUBJECTS WITH MYELOFIBROSIS (MF) ADMINISTERED
WITH RUXOLITINIB. X. Chen, X. Liu, S. Peng, W. V. Williams,
V. Sandor, S. Yeleswaram; Incyte Corp., Wilmington, DE. X. Chen:
None. X. Liu: None. S. Peng: None. W.V. Williams: None. V. Sandor:
None. S. Yeleswaram: None.
BACKGROUND: A population PK/PD model was developed to
characterize the time course of spleen volume in MF patients treated
with ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2.
METHODS: Data from a Phase 2 and a Phase 3 study were used
as the modeling dataset. Data from a second Phase 3 study was used
for validation. Population PK/PD analysis was conducted sequentially.
The average daily steady-state plasma concentrations (Cave) derived
from the population PK model were used as an exposure measure.
An indirect response (IDR) model was used to characterize the time
course of spleen volume. An inhibitory E max function was applied to
the formation rate constant for response. Covariates evaluated included
age, gender, weight, race, JAK2V617F mutation, MDRD GFR, total
bilirubin, MF duration etc.
RESULTS: The modeling dataset included 919 spleen volume
measurements from 253 subjects. The external validation dataset
contained 592 spleen volume measurements from 128 subjects. The
structural PK/PD model was parameterized in terms of k in and k out
describing the increase and decrease in spleen volume, respectively.
An E plc of 0.0505 describes the small increment in spleen volume over
time in the absence of drug. Gender and JAK2V617F mutation status
were significant predictors of the IC 50 for spleen volume reduction.
The typical I max was a decrease of 0.765 the typical IC 50 was estimated
at 414 nM and 206 nM for males who are negative and positive for
the JAK2V617F mutation, respectively, and 244 nM and 122 nM for
females who are negative and positive for the JAK2V617F mutation,
respectively. The typical Cave for 15 mg BID was 202 nM. Visual predictive
check and external validation showed that the exposure-spleen
volume relationship was adequately described by the model.
CONCLUSION: Gender and JAK2V617F mutation status were
statistically significant predictors of the IC 50 for spleen volume reduction
by ruxolitinib in MF patients.
PI-99
POPULATION PK/PD ANALYSIS OF TOTAL SYMPTOM
SCORE (MFSAF) IN SUBJECTS WITH MYELOFIBROSIS (MF)
TREATED WITH RUXOLITINIB. X. Chen, X. Liu, S. Peng, W. V.
Williams, V. Sandor, S. Yeleswaram; Incyte Corp., Wilmington, DE.
X. Chen: None. X. Liu: None. S. Peng: None. W.V. Williams: None.
V. Sandor: None. S. Yeleswaram: None.
BACKGROUND: A population PK/PD model was developed to
characterize the time course of MFSAF in MF patients treated with
ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2.
METHODS: Data from a Phase 3 study was used as the modeling
dataset; no external validation dataset was available. The MFSAF was
collected daily from 7 days prior to the first dose through week 24 and
included symptoms of night sweats, itching, abdominal discomfort,
pain under ribs on left, feeling of fullness (early satiety), and muscle/
bone pain. Population PK/PD analysis was conducted sequentially.
The average daily steady-state plasma concentrations derived from
the population PK model was selected as an exposure measure. The
MFSAF was modeled with a modified indirect response (IDR) model,
in which a logit transformation was implemented to constrain model
predictions between scores of 0 and 60; the drug effect was characterized
via an inhibitory E max function applied to the first-order equilibration
rate constant (k out ).
RESULTS: The dataset contained 1,566 data points from 242
subjects. The mean population estimate of I max was 58 and the IC 50
was 233 nM, indicating a substantial reduction in MFSAF at average
ruxolitinib plasma concentrations achieved with ≥10 mg BID dosing
regimens. A placebo effect on the production of response was included
in the model by incorporating an E plc fixed effect term describing a
proportional shift in k out . Baseline MFSAF and blood transfusion
status were each statistically significant predictors of E plc . No statistically
significant covariates were identified for MFSAF change induced
by ruxolitinib. The visual predictive check showed that MFSAF was
described adequately by the model.
CONCLUSION: The time course of MFSAF could be adequately
described by a modified IDR model and no subpopulations with altered
MFSAF in the presence of ruxolitinib were identified.
PI-100
TOLVAPTAN PHARMACOKINETICS (PK) AND PHARMACO-
DYNAMICS (PD) IN HEALTHY CAUCASIAN AND JAPANESE
MEN FOLLOWING 30 MG IN EITHER THE FASTED STATE
OR FOLLOWING A HIGH FAT MEAL OR JAPANESE STAND-
ARD MEAL. S. E. Shoaf, 1 S. Kim, 2 P. Bricmont, 1 S. Mallikaarjun 1 ;
1 Otsuka Pharmaceutical Development & Commercialization, Inc,
Rockville, MD, 2 Otsuka Pharmaceutical Co., Ltd., Osaka, Japan.
S.E. Shoaf: 2. I am a paid consultant/employee for; Company/Drug;
OPDC. S. Kim: 2. I am a paid consultant/employee for; Company/
Drug; OPC-J. P. Bricmont: 2. I am a paid consultant/employee for;
Company/Drug; OPDC. S. Mallikaarjun: 2. I am a paid consultant/
employee for; Company/Drug; OPDC.
BACKGROUND: Tolvaptan (TLV) is a selective vasopressin receptor
(V 2 ) antagonist approved in the US and Europe for hyponatremia
and in Japan for volume overload in heart failure when adequate
response is not obtained with other diuretics. A combined race and
comparative food effect trial was conducted for bridging purposes.
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METHODS: An open-label, parallel-arm, 3-period, randomized,
crossover trial was conducted to determine the effect of food (US FDA
high fat meal [HFM] and Japanese standard meal [JSM, 600 calories,
21% fat, 2.1 g sodium]) on the PK and PD of TLV in 24 Japanese and
25 Caucasian healthy men. Each group was randomized to be administered
a single oral 30 mg dose in the fasted state or immediately following
a HFM or JSM; doses were separated by 72 h. Serial blood samples
for a noncompartmental PK analysis were obtained for 48 h postdose.
Urine volume and fluid intake were monitored for 24 h postdose.
RESULTS: TLV concentrations were higher in Japanese men in the
fasted and HFM states, most likely due to lower body weight as body
weight adjusted clearance values were similar. A HFM increased TLV
exposure 12-18% in both groups. A JSM increased TLV exposure
10-18% in Japanese men but only 2-6% in Caucasian men. Fluid balance
was significantly lower in Japanese men. Administration with food produced
no clinically significant differences in 24-hour urine volume.
CONCLUSION: TLV PK is not affected by race; body weight is a
factor that affects exposure. TLV can be administered with or without
food.
Mean (SD) PK and PD Parameters Following 30 mg Tolvaptan
Caucasian (n=24) Japanese (n=24)
Parameter Fasted HFM JSM Fasted HFM JSM
C max (ng/mL)
AUC ∞
(μg·h/mL)
CL/F
(mL/min/kg)
Change From
Baseline in
24-hour Urine
Volume (L)
Change From
Baseline in
24-hour Fluid
Balance (L)
247
(71.0)
1.44
(0.46)b
5.14
(1.85)b
4.45
(1.77) f
-0.83
(0.66) f
319
(175)
1.71
(0.71)c
4.65
(2.23)c
5.28
(1.75) f
-0.64
(1.35) f
a n=22, b n=19, c n=17, d n=21, e n=20, f n=23
273
(113)
1.58
(0.72)d
5.19
(2.49)d
4.93
(1.94) f
-0.80
(1.18) f
273
(80.7)
1.73
(0.76)e
5.36
(2.09)e
4.57
(1.79)
-1.17
(0.83)
320
(129)
2.04
(0.91)e
4.64
(1.98)e
5.45
(2.07)
-1.27
(1.01)
335
(157)a
2.01
(1.02)e
4.83
(2.03)e
5.21
(2.02)a
-1.58
(1.30)a
PI-101
ASSEMBLING OF A MULTICENTER AND MULTINATIONAL
DATA BASE TO DEVELOP AND VALIDATE A PHYSIOLOGI-
CALLY BASED PHARMACOKINETIC SOTALOL MODEL FOR
PEDIATRIC EXTRAPOLATION. F. Khalil, S. Laeer; Department of
Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University
of Duesseldorf, Duesseldorf, Germany. F. Khalil: None. S. Laeer:
None.
BACKGROUND: Physiology based models arise as an attractive
tool to extrapolate and explore drug disposition from adults into children
by incorporating information about organs growth and development.
Such models are, however, associated with uncertainty and might
be biased, especially when only adult data sets from single center pharmacokinetic
trials are used during model development and validation.
Therefore, a multicenter, multinational pharmacokinetic data base was
collected to develop and validate a physiology based pharmacokinetic
adult model for sotalol.
METHODS: Literature was screened to collect multiple pharmacokinetic
adult sotalol data sets. Simcyp simulator v.11 was used to
develop a PBPK model of sotalol using the necessary input parameters
including drug physicochemical properties. Then, simulations were
performed to match the collected populations and trials’ conditions.
The results of predicted plasma profiles were presented with observed
data for visual inspection. As quantitative measure of model performance,
AUC 0-tlast ratio of observed versus predicted was reported.
RESULTS: A total of 11 clinical trials (1976 to 2010) by 8 different
scientific groups in 5 countries incorporating 139 healthy subjects
were included in the model development and validation for intra-
aBsTraCTs
venous and oral dosing of sotalol. The developed model of sotalol
allowed a close agreement between all observed and predicted concentration
vs. time profiles. The mean AUC 0-tlast ratio of 0.97 ranged
between 0.82-1.18.
CONCLUSION: The presented model was able to appropriately
reflect various clinical trials in adults under various conditions for both
intravenous and oral application. This model is now ready to extrapolate
into the pediatric population to explore the effects of organ maturation
and ontogeny on sotalol pharmacokinetics.
PI-102
POPULATION PHARMACOKINETICS OF VORICONAZOLE
IN HUMAN PLASMA AND AQUEOUS HUMOUR AFTER ORAL
ADMINISTRATION. Y. Daali, L. Cottet, M. Gex-Fabry, P. Dayer,
E. Baglivo, J. Desmeules; Geneva University Hospitals, Geneva,
Switzerland. Y. Daali: None. L. Cottet: None. M. Gex-Fabry: None.
P. Dayer: None. E. Baglivo: None. J. Desmeules: None.
BACKGROUND: Voriconazole (VRZ) is an antifungal azole used
for the treatment of fungal endophthalmitis. Its ocular penetration and
pharmacokinetics in the eye are still unknown. The purpose of the
current study was to evaluate the pharmacokinetics of VRZ in human
aqueous humour and plasma after oral administration using a population
pharmacokinetic approach.
METHODS: 34 patients undergoing cataract surgery received
200 mg VRZ at various times before surgery. The concentrations of
VRZ in both plasma (103 samples, 2-3 per patient) and aqueous humour
(34 samples, 1 per patient) were determined by high-performance liquid
chromatography with fluorescence detection. Population pharmacokinetic
software NONMEM was used to calculate pharmacokinetic
parameters in the eye and plasma, as well as the influence of various
covariates. The following covariables were investigated for a possible
influence on model parameters: age, sex, weight, CYP2C19, CYP2C9
and CYP3A4 phenotypes.
RESULTS: VRZ concentrations in both plasma and aqueous
humour were adequately described with a two-compartment open
model with first order transfer rates. Final population estimates were:
ka (h -1 ) = 3.04 (CV 51.6%), CLp (l/h) = 19.7 (CV 16.0%), Vp (l) =
175 (CV 10.5%), kap (h -1 ) = 1.44 (CV 25.4%). Among covariates,
CYP2C19 phenotype and sex significantly influenced elimination of
voriconazole. The clearance of VRZ increased with CYP2C19 activity
and decreased in females. The penetration of VRZ in the eye, described
by the ratio (kpa.Vp/kap.Va), was 0.52.
CONCLUSION: The selected population model successfully characterized
VRZ pharmacokinetics in both plasma and aqueous humour
and allowed to identify significant covariates. Moreover it was possible
to quantify ocular penetration of voriconazole after oral administration.
PI-103
PAIN PERCEPTION AND PROCESSING IN A MEDICATED
STATE: A PILOT STUDY IN AN ELDERLY COHORT. A. Edginton, 1
K. Schaffler 2 ; 1 University of Waterloo, Waterloo, ON, Canada, 2 HPR
Dr. Schaffler GmbH, Munich, Germany. A. Edginton: 1. This research
was sponsored by; Company/Drug; HPR Dr. Schaffler GmbH,
Munich, Germany. K. Schaffler: 1. This research was sponsored by;
Company/Drug; HPR Dr. Schaffler GmbH, Munich, Germany. 2. I
am a paid consultant/employee for; Company/Drug; HPR Dr. Schaffler
GmbH, Munich, Germany.
BACKGROUND: Advanced age is associated with increased
prevalence of chronic pain, increased pain threshold and decreased tolerance
to supra-threshold pain; as is common in clinical pain states.
Due to these differences, it is of interest to assess the age-dependence
of objective [Laser induced somatosensory evoked potentials (LEPs)
from Vertex-EEG] and subjective [Visual Analogue Scale (100mm
VAS)] measures of pain and the potential for differential efficacy of
anti-hyperalgesic medication.
METHODS: This pilot-study was a randomized, single-dose (1000
mg acetaminophen), placebo-controlled, 2-sequence intra-individual
CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s45

aBsTraCTs nature publishing group
crossover study including 6 (3 male, 3 female) participants over the
age of 65 [66-69]. LEPs and VAS scores were measured over a 5 hour
period following noxious stimuli to untreated and UVB-irradiated
(hyperalgesic) skin with and without medication.
RESULTS: On untreated and UVB-irradiated skin, the LEP amplitudes
of the PtP (Peak-to-Peak) -component appear smaller than in
younger historical controls. PtP-amplitude reduction by medication
was more accentuated in UVB than in untreated skin with a predominant
anti-hyperalgesic effect vs. placebo in LEPs and VAS starting
1-2 hours post-administration. The mean VAS score was always lower
compared to a previous study of 24 young adult participants (Figure).
CONCLUSION: This study presents evidence that the extent of
nociceptive impact and medication may differ by age. A full PK/PD
study comparing young and older adults is planned.
VAS (mm)
60
50
40
30
20
60
50
Young adult, placebo (n=21)
Young adult, acetaminophen (n=24)
Older adult, placebo (n=6)
Older adult, acetaminophen (n=6)
untreated
40
30
UVB Mean baseline, untreated skin
20
0 1 2 3 4 5
Hours post-administration
PI-104
A PROBABILISTIC RISK ASSESSMENT OF BREAST CANCER
TREATMENT FAILURE DURING CO-ADMINISTRATION OF
TAMOXIFEN AND PAROXETINE AS IT RELATES TO CYP2D6
GENOTYPE. A. Edginton, 1 M. Sevestre, 2 J. Stingl 3 ; 1 University of
Waterloo, Waterloo, ON, Canada, 2 Design2Code, Waterloo, ON,
Canada, 3 Univerity of Ulm, Ulm, Germany. A. Edginton: None.
M. Sevestre: 2. I am a paid consultant/employee for; Company/Drug;
Bayer Technology Services GmbH. J. Stingl: None.
BACKGROUND: Tamoxifen is a prodrug metabolized by CYP2D6
to its active metabolite, Z-endoxifen. A CYP2D6 polymorphism resulting
in poor (PM), intermediate (IM) and extensive (EM) metabolizers,
contributes to PMs being 40% more likely to relapse than EMs.
Paroxetine, used for hot flash prevention during tamoxifen use, is an
irreversible CYP2D6 inhibitor. The risk of sub-therapeutic Z-endoxifen
concentrations with concomitant use may vary with CYP2D6 status.
This study aims to bridge clinical gaps with pharmacometric analysis
to assess tamoxifen dose requirements during paroxetine use.
METHODS: Coupled whole-body population physiologically
based pharmacokinetic (PBPK) models for paroxetine (20 mg/d)
and tamoxifen (20 mg/d for 4 months) + metabolites (desmethyltamoxifen,
Z-4-OH-tamoxifen, Z-endoxifen) were developed using in
vitro and clinical data, and included CYP2D6 inhibition in the presence
of paroxetine.
RESULTS: The estrogen-receptor inhibiting capacity of the majority
of PMs does not reach 90% (IC90_endoxifen= 12.5 nmol/L) (Figure).
In the presence of paroxetine, there is an 80% (EM), 43% (IM)
and 27% (PM) chance of reaching the IC90. IMs receiving paroxetine
require 40 mg/d tamoxifen to have 90% of IMs over the IC90, although
this may not be feasible.
CONCLUSION: Tamoxifen administration to PMs has a high
probability of failure. While the efficacy of 20 mg/d tamoxifen for EM
and IMs is reasonable, in the presence of paroxetine, there is a high
chance of treatment failure for IMs but not EMs.
PI-105
THE UTILITY OF PROBABILISTIC SIMULATION IN DRUG
RISK-BENEFIT ASSESSMENT IN OLDER ADULTS. J. Lee,
V. Crentsil; U.S. Food and Drug Administration, Silver Spring, MD.
J. Lee: None. V. Crentsil: None.
BACKGROUND: Establishing a drug dosage that balances benefit
and risk in older adults can be challenging; we demonstrate utility of
probabilistic simulation for that purpose.
METHODS: Our study population were schizophrenics aged
>50 years, on olanzapine > 2 weeks, and non-diabetic at baseline,
from the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE). Benefit is defined as ≥ 20% reduction from baseline total
PANSS score and risk as postbaseline fasting glucose > 100mg/dl.
We estimated the benefit and risk probabilities of oral daily dosages
of 7.5, 15, and 30 mg. After using the benefit-risk plane to explore
favorable doses, we used Monte Carlo [MC] simulation (N=5000) to
determine the distribution of benefit and risk probabilities for each
dose. We then used benefit-risk acceptability curves to determine the
proportion of benefit-risk joint density below benefit risk preference
value of one.
RESULTS: Study patients (N=34) were male (82.3%), average
age 54.4 years, Caucasian (67.6%), and average treatment duration of
361.8 days. Benefit and risk probabilities were 0.5 each for 7.5 mg; 0.6
each for 15 mg, and benefit probability was 0.57 and risk 0.67 for 30
mg. Only 30 mg was beyond acceptability preference of the benefitrisk
plane. MC simulation revealed mean probability of benefit as 0.49
and risk 0.50 for 7.5 mg; 0.6 each for 15 mg, and mean probability of
benefit as 0.57 and risk 0.67 for 30 mg. The benefit-risk acceptability
curves showed that the proportion of benefit-risk joint density below
preference value was 0.4999 for 7.5 mg, 0.5104 for 15 mg, and 0.3410
for 30 mg (optimal is > 0.5).
CONCLUSION: This study introduces an innovative approach
for finding the safe dose without extensive exposure of a vulnerable
population to drugs. Our study suggests 15 mg a day of olanzapine as
optimal for the balance of therapeutic benefit and risk of glucose intolerance
for this study population. Our results are not generalizable due
to small sample size.
s46 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt
Z-endoxifen concentration (nmol/L)
100
10
a EM; n=88
No Paroxetine
b
EM; n=100
a
IM; n=129
b
IM; n=100
a
Murdter et al. 2011
b
simulation
c
Stearns et al. 2003
IC90 (Estrogen Receptor)
a PM; n=14
b PM; n=100
c EM; n=7
With Paroxetine
b EM; n=100
c
IM+PM; n=5
b
IM; n=100
b
PM; n=100

nature publishing group
PI-106
USING MODELING AND SIMULATION TO OPTIMIZE DRUG
RISK-BENEFIT IN OLDER ADULTS. V. Crentsil, J. Lee, A. Jackson;
U.S. Food and Drug Administration, Silver Spring, MD. V. Crentsil:
None. J. Lee: None. A. Jackson: None.
BACKGROUND: Establishing a drug dosage that balances benefit
and risk in older adults can be challenging; we demonstrate utility of
modeling and simulation for that purpose.
METHODS: The study population were schizophrenics >50 years,
on olanzapine > 2 weeks, and non-diabetic at baseline, from the Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE). Benefit
is defined as ≥ 20% reduction in baseline total PANSS score and risk
as postbaseline fasting glucose > 100mg/dl. A published mixed-effects
model with covariates for sex, race, and smoking was used to calculate
AUC. Benefit-risk AUC breakpoint (bp-AUC) was determined from
mean AUC of benefit and risk patient groups and confirmed by Monte
Carlo [MC] simulation (N=5000) and benefit-risk acceptability curve.
Using multivariate regression, we estimated olanzapine dose corresponding
to bp-AUC. MC simulation (N=5000) was used to estimated
uncertainty around olanzapine dose.
RESULTS: Study population (N=34) were on average aged 54.4
years, therapy duration of 361.8 days, male (82.3%) and Caucasian
(67.6%). Mean AUC was 747.6 ng.hr /ml [95% CI: 524.5, 970.7] for
benefit group (N=16) and 754.1 [95% CI: 505.9, 1002.4] for risk group
(N=15). The bp-AUC was 524.5 ng.hr/ml; the proportion of riskbenefit
pairs below the acceptability threshold of 1 for bp-AUC was
51%, confirming acceptability. Using our derived regression equation
below, the mean oral olanzapine dose corresponding to bp-AUC was
17.8 mg/ day: Dose = -54.34 + 11.53 • ln AUC + 1.21 • SEX - 3.07
• RACE + 2.16 • SMOKE MC simulation (N=5000) yielded a mean
dose of 17.81 mg (95% CI: 17.76, 17.87).
CONCLUSION: This study demonstrates utility of modeling and
simulation to estimate the optimal drug dose that preserves benefit and
limit risk. Our results suggest that for our study population, olanzapine
dose at which therapeutic benefit and risk for glucose intolerance is
balanced is 17.8 mg/day. Generalizability of our results is limited by
small sample size.
OII-A-1
NOVEL TRANSLATIONAL PARADIGM FOR DRUG-DRUG
INTERACTION RESEARCH: A COMBINATION OF LITERA-
TURE-BASED DISCOVERY, ELECTRONIC MEDICAL RECORDS
AND IN VITRO DDI SCREENING ASSAYS. X. Han, 1 Z. Wang, 2 A.
Subhadarshini, 2 S. Karnik, 2 R. M. Strother, 3 S. D. Hall, 4 Y. Jin, 4 D. A.
Flockhart, 5 S. K. Quinney, 6 J. D. Duke, 7 L. Li 8 ; 1 Department of Pharmacology
and Toxicology, Indiana University School of Medicine,
Indianapolis, IN, 2 Center for Computational Biology and Bioinformatics,
Indiana University School of Medicine, Indianapolis, IN, 3 Division
of Hematology/Oncology, Department of Medicine, Indiana University
School of Medicine, Indianapolis, IN, 4 Eli Lilly INC, Indianapolis,
IN, 5 Division of Clinical Pharmacology, Department of Medicine,
Indiana University School of Medicine, Indianapolis, IN, 6 Department
of Obstetrics/Gynecology, Indiana University School of Medicine,
Indianapolis, IN, 7 Regenstrief Institute, Indiana University School
of Medicine, Indianapolis, IN, 8 Department of Medical and Molecular
Genetics, Indiana University School of Medicine, Indianapolis,
IN. X. Han: None. Z. Wang: None. A. Subhadarshini: None. S.
Karnik: None. R.M. Strother: None. S.D. Hall: 2. I am a paid consultant/employee
for; Company/Drug; Eli Lilly. Y. Jin: 2. I am a paid
consultant/employee for; Company/ Drug; Eli Lilly. D.A. Flockhart:
None. S.K. Quinney: None. J.D. Duke: None. L. Li: None.
BACKGROUND: Only a limited number of drug-drug interactions
(DDIs) can be investigated in the traditional pharmacology study
paradigm. Using novel biomedical informatics tools, electronic medical
record (EMR) databases and in vitro DDI screening assays, we
explored a new translational DDI research paradigm.
aBsTraCTs
METHODS: CYP450 enzyme substrates and inhibitors were identified
from Pub Med abstracts by text mining. A substrate and an inhibitor
of the pertinent CYP formed a predicted DDI. In a de-identified
EMR data set from the Indiana Patients Care database (n = 2.2 million),
each predicted DDI effect on myopathy was tested by a z-score
test. The type I error was Bonferroni corrected. The relative risk (RR)
was adjusted by age, gender, race, and symptom.
RESULTS: 13,117 DDI pairs were predicted from text mining. Six
predicted DDIs are significantly associated with increased myopathy
risk (p 500 14 1.3 23.8 6.3 24.4 CYP3A4,
CYP2D6
Duloxetine +9.6 34.4 30.4 7 1.1 10.7 CYP2D6,
CYP1A2
Omeprazole 91.2 NA NA 34.4 208.3 10.2 CYP2C19,
CYP3A4
8615885
12621382
16093273
Simvastatin >100 46 7.4 55.8 53.5 4.8 CYP3A 9321523
Ropinirole 807.6 >500 >1000 >1000 1 782.4 CYP1A2,
CYP3A
9224778
Promethazine 1.2 58.9 55.5 33.5