Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin.
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.
Schwartz
Jules I
JI
Merck & Co., Inc., Rahway, New Jersey, USA. schwartj@gmail.com
Dunbar
Stephanie
S
Yuan
Jinyu
J
Li
Susie
S
Gipson
Adrianna
A
Rosko
Kim
K
Johnson-Levonas
Amy O
AO
Lasseter
Kenneth C
KC
Addy
Carol
C
Stoch
Aubrey S
AS
Wagner
John A
JA
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
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