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American Society for Clinical Pharmacology and Therapeutics
RIMONABANT PHARMACOKINETICS IN HEALTHY AND
CYP3A5 BUT NOT CYP2D6 POLYMORPHISM AFFECTS
OBESE SUBJECTS. S. Turpault, V. Kanamaluru, G. F. Lockwood,
DEXTROPROPOXYPHENE DISPOSITION IN HUMAN SUB-
D. Bonnet, J. Newton, sanofi-aventis, Malvern, PA.
JECTS. M. S. Chow, PharmD, O. Q. Yin, PhD, B. Tomlinson, MD,
Rimonabant is the first selective CB1 blocker
The Chinese University of Hong Kong, Shatin, New Territories Hong
developed for the management of multiple cardiometabolic risk fac-
Kong Special Administrative Region of China.
To assess the pharmacokinetics (PK) of rimonabant after
(DEX) to its major metabolite nordextropropoxyphene has been
repeated oral doses in healthy and obese subjects.
reported to be mediated via CYP2D6 and 3A in in vitro studies. In
PK was assessed in healthy young non-obese males
this study we evaluated the relative effect of CYP2D6, 3A4 and 3A5
in a randomized, double-blind, placebo-controlled, ascending dose
polymorphism on DEX disposition in human subjects.
study after 3, 10, 20, 40 and 60 mg once-daily doses for 21 days
Fourteen healthy male subjects received a single
(Nϭ8 active, 2 placebo/group). PK was assessed in young obese
32.5 mg DEX and 325 mg paracetamol (Cosalgesic tablet). Multiple
subjects (BMIՆ30 kg/m2) in an open label study after 20 mg once-
blood samples were collected over 24 h, and plasma concentrations of
daily doses for 21 days (Nϭ8/gender). Blood was sampled after the
DEX and paracetamol were determined by an LC-MS-MS method.
first and last dose for full PK profiles and at pre-dose on specified
CYP2D6, 3A4 and 3A5 genotyping were performed using the re-
days. Plasma was analyzed for rimonabant with a validated LC-
No CYP3A4 mutant alleles (ء4, ء5 and ء6) were
Mean (SD) non-compartmental PK parameters of
detected. There were no significant differences in DEX pharmacoki-
netics among subjects with different CYP2D6 genotype (ANOVApϾ0.05). However, DEX plasma concentration was significantly
higher in CYP3A5ء3/ء3 (nϭ8) than ء1/ء3 (nϭ5) or ء1/ء1 (nϭ1)subjects, and their respective apparent oral clearance were
2.26Ϯ0.93, 3.60Ϯ1.56, and 12.5 L/h/kg (ANOVA pϽ0.05). The
pharmacokinetics of paracetamol was similar among subjects with
326 (92.5) 3.00 (2.00, 5.98) 4830 (1360) 193 (73.3)
CYP3A5 but not 2D6 polymorphism appears
416 (90.6) 3.50 (1.50, 6.02) 6760 (1560) 151 (59.3)
to exert a significant influence on DEX disposition. Subjects withCYP3A5ء1/ء1 genotype may be “ultrarapid” metabolizers of DEX,
a: median (min, max); b: t ϭtime to reach steady-state, median (90th
which could possibly lead to accumulation of toxic nordextro-
propoxyphene in the body. Further studies with larger number ofsubjects are needed to verify these findings.
Rimonabant exhibits no major deviation from
dose proportionality up to 20 mg (therapeutic dose range), afterwhich there is a less than dose-proportional increase in exposure.
Obese subjects have a longer t
(6 to 9 days) due to a larger peripheral volume of distribution. Genderhas no effect on rimonabant PK.
RETROSPECTIVE POPULATION PHARMACOKINETIC ANALY-
SIS OF LEVETIRACETAM IN WESTERNER AND JAPANESEADULTS. E. Pigeolet, P. Jacqmin, M. Sargentini-Maier, A. Stockis,UCB, Clinical Pharmacology, Exprimo, Braine l’Alleud, Belgium.
Two matched study sets were used to identify
SIX-DAY CONTINUOUS IV INFUSION STUDY OF THE
demographic and/or physiologic determinants of levetiracetam
SAFETY, TOLERABILITY, AND PK OF ASCENDING DOSES
(LEV) in Westerner and Japanese adults.
OF ROTIGAPTIDE (ZP123) IN HEALTHY SUBJECTS. C. Udata,
Plasma concentration-time data (nϭ5408), together
PhD, M. Micalizzi, RN, MS, A. Katz, MD, Q. M. Giorgio, MD, X.
with demographic and treatment information, from 524 subjects in 6
Phase I, 2 Phase III and 2 long-term follow-up studies of add-on
To assess the safety, tolerability, and
LEV. A 1-compartment, open model was used, with 1st order ab-
pharmacokinetics of 6-day continuous intravenous infusion of roti-
sorption and elimination. Inter-subject variability was modeled using
gaptide, a first-in-class cardiomyocyte gap junction modifier, in
exponential function, and residual variability by 2 proportional error
models; 1 for healthy subjects and 1 for patients with epilepsy.
This was a randomized, double-blind, placebo-
Inter-occasion variability term was used for absorption.
controlled, sequential-group study of ascending doses of rotigaptide.
Body weight (BW), gender, creatinine clearance and
Rotigaptide or placebo was administered to 32 men as a 6-day
concomitant (1-3) antiepileptic drugs significantly affected LEV
continuous IV infusion at doses of 1 to 20 mg/day. Safety was
clearance. BW, health status and valproate (VPA) significantly af-
determined from reported adverse events (AEs), physical exams, vital
fected volume of distribution (Vd). Ethnicity was not a statistically
signs, laboratory tests, and 12-lead ECGs. Plasma and urine samples
significant covariate. Clearance varied by a maximum of 20% when
were analyzed for rotigaptide using a validated LC/MS/MS method
BW was halved or doubled from the population mean. Clearance was
and rotigaptide pharmacokinetics was characterized.
increased 9% by inducers and decreased 19% by VPA. Vd increased
The most common AEs were IV site reactions
linearly with BW, and decreased by 23% with VPA. LEV exposure
(nϭ14), orthostatic pulse and blood pressure changes (nϭ11), appli-
was increased approximately 20% by frail BW and VPA, but not
cation site reactions (nϭ5), and increased ALT (nϭ3) and AST
considered clinically relevant, given LEV’s low toxicity and recom-
(nϭ2). All were considered as mild or moderate and probably not
related to test article. There were no dose-related trends in AEs or
Several explanatory covariates contributing to
laboratory tests. Rotigaptide mean steady-state concentrations ranged
LEV’s modest pharmacokinetic variability were identified. There
from 6.28 to 90.6 ng/mL on day 1 and 5.70 to 97.7 ng/mL on day 6
were no differences between ethnicities.
and were consistent with the predicted levels based on the single-dosePK. AUC
increased in a dose-proportional manner. About 65-84%
excreted unchanged in urine and no metabolites were apparent inplasma.
Rotigaptide appeared to be safe and well-
tolerated at the doses tested. Rotigaptide showed predictable, doseand time-independent pharmacokinetics.
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