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, BACKGROUND: 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.
AIMS: 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 METHODS: 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 METHODS: 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- RESULTS: No CYP3A4 mutant alleles (ء4, ء5 and ء6) were
RESULTS: 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 Subjects (mg)
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) CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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, METHODS: 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 BACKGROUND/AIMS: 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.
METHODS: This was a randomized, double-blind, placebo-
Inter-occasion variability term was used for absorption.
controlled, sequential-group study of ascending doses of rotigaptide.
RESULTS: 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 RESULTS: 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 CONCLUSION: 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.
CONCLUSION: Rotigaptide appeared to be safe and well-
tolerated at the doses tested. Rotigaptide showed predictable, doseand time-independent pharmacokinetics.


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