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Schwartz JI, Dunbar S, Yuan J, Li S, Gipson A, Rosko K, Johnson-Levonas AO, Lasseter KC, Addy C, Stoch AS, Wagner JA: Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin. Cardiol Clin. 2008 May;26(2):169-87
INTRODUCTION: The pharmacokinetic/pharmacodynamic effects of warfarin were assessed in the presence and absence of taranabant, an orally active, highly selective, potent, cannabinoid-1 receptor inverse agonist, which was being developed for the treatment of obesity. METHODS: Twelve subjects were assigned to two open-label treatments in fixed sequence separated by a 14-day washout. Treatment A was single-dose warfarin 30 mg on day 1. Treatment B was multiple-dose taranabant 6 mg each day for 21 days (days -14 to day 7) with coadministration of singledose warfarin 30 mg on day 1. Blood samples were collected predose and up to 168 hours postdose for assay of R (+)-and S (-)-warfarin and prothrombin time/international normalized ratio (PT/INR). RESULTS: The geometric mean ratios (GMR; warfarin+taranabant/warfarin 90% confidence interval [CI] primary endpoints) for area under the curve (AUC)(0-infinity) for R (+)-and S (-)-warfarin were 1.10 (90% CI: 1.03, 1.18) and 1.06 (90% CI: 1.00, 1.13), respectively. The GMRs (warfarin+taranabant/warfarin) for the maximum plasma concentration (C (max)) of S (-)-and R (+)-warfarin were 1.16 (90% CI: 1.05, 1.28) and 1.17 (90% CI: 1.07, 1.29), respectively. For R (+)-and S (-)-warfarin, the 90% CIs for AUC (0-infinity) GMRs fell within the prespecified bounds. Taranabant did not produce a clinically meaningful effect on PT/INR. CONCLUSION: No clinically significant alterations of the pharmacokinetics of R (+)-and S (-)-warfarin were seen following coadministration of multipledose taranabant 6 mg and single-dose warfarin 30 mg. |
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