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

• Published in: Advances in therapy Vol. 25; no. 11; pp. 1175 - 1190
• Main Authors: Schwartz, Jules I., Dunbar, Stephanie, Yuan, Jinyu, Li, Susie, Gipson, Adrianna, Rosko, Kim, Johnson-Levonas, Amy O., Lasseter, Kenneth C., Addy, Carol, Stoch, Aubrey S., Wagner, John A.
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Healthcare Communications 01.11.2008
• Subjects: Adult; Amides - pharmacology; Anticoagulants - chemistry; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Appetite Depressants - pharmacology; Area Under Curve; Cardiology; Drug Inverse Agonism; Endocrinology; Female; Half-Life; Hispanic Americans; Humans; Internal Medicine; International Normalized Ratio; Male; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Oncology; Original Research; Pharmacology/Toxicology; Prothrombin Time; Pyridines - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Rheumatology; Warfarin - chemistry; Warfarin - pharmacokinetics; Warfarin - pharmacology; Young Adult; taranabant; pharmacodynamics; pharmacokinetics; cannabinoid-1 receptor inverse agonist; obesity; CB1R; warfarin
• ISSN: 0741-238X; 1865-8652; 1865-8652
• DOI: 10.1007/s12325-008-0116-9

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.