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The Effect of Etoricoxib on the Pharmacodynamics and Pharmacokinetics of Warfarin

From Merck Research Laboratories, Rahway, New Jersey, and West Point, Pennsylvania (Dr Schwartz, Dr Agrawal, Dr Hartford, Ms Cote, Dr Gottesdiener); PPD-Inc, Austin, Texas (Dr Hunt, Mr Eckols); and Katholieke Universiteit Leuven, Department of Pharmacology, Campus Gasthuisberg, Leuven, Belgium (Dr Verbesselt).

The effects of etoricoxib on pharmacodynamic and pharmacokinetic parameters of warfarin were determined in healthy men and women. Subjects titrated with warfarin to an international normalized ratio for prothrombin time of 1.4 to 1.7 during a 28-day prestudy period were randomly assigned in crossover fashion to be coadministered etoricoxib (120 mg) or matching placebo over two 21-day continuous periods. On day 21, a 24-hour pharmacokinetic profile of both S(-) and R(+) warfarin, as well as international normalized ratio values, were determined. Etoricoxib increased the international normalized ratio by 13% (90% confidence interval: 8%, 19%; P .001). Etoricoxib had no effect on the pharmacokinetics of S(-) warfarin but led to a modest increase in the AUC_{24 h} (10%) of R(+) warfarin. This increase in the international normalized ratio is not likely to be clinically important in most patients; however, the international normalized ratio of patients coadministered oral anticoagulants and etoricoxib should be closely monitored, particularly during initiation of therapy.

Key Words: Drug interaction • warfarin • etoricoxib • steady state

Address for reprints: Address for correspondence: Jules I. Schwartz, PharmD, MPH, Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, PO Box 2000, RY34-A552, Rahway, NJ 07065-0900; e-mail:jules_schwartz{at}merck.com.