Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

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 (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-∞ 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.