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

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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