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

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