Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin |
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Authors: | Jules I. Schwartz Stephanie Dunbar Jinyu Yuan Susie Li Adrianna Gipson Kim Rosko Amy O. Johnson-Levonas Kenneth C. Lasseter Carol Addy Aubrey S. Stoch John A. Wagner |
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Affiliation: | (1) Merck & Co., Inc., Rahway, New Jersey, USA;(2) Clinical Pharmacology of Miami, Miami, Florida, USA;(3) Present address: Pfizer Inc., New York, New York, USA;(4) Department of Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ, USA |
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Abstract: | 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-∞ 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 (Cmax) 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 AUC0-∞ 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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Keywords: | cannabinoid-1 receptor inverse agonist CB1R obesity pharmacodynamics pharmacokinetics taranabant warfarin |
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