title: Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA. schwartj@gmail.com
authors.forename: Jules I
authors.initials: JI
authors.lastname: Schwartz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dunbar
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yuan
authors.forename: Susie
authors.initials: S
authors.lastname: Li
authors.forename: Adrianna
authors.initials: A
authors.lastname: Gipson
authors.forename: Kim
authors.initials: K
authors.lastname: Rosko
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
authors.forename: Carol
authors.initials: C
authors.lastname: Addy
authors.forename: Aubrey S
authors.initials: AS
authors.lastname: Stoch
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000328:Adult; D000577:Amides / Q000494:pharmacology*; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001067:Appetite Depressants / Q000494:pharmacology*; D019540:Area Under Curve; D054314:Drug Inverse Agonism; D005260:Female; D006207:Half-Life; D006630:Hispanic or Latino; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000577:Amides; D000925:Anticoagulants; D001067:Appetite Depressants; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D014859:Warfarin; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide