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The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin
Author(s) -
Schwartz Jules I.,
Bugianesi Kathleen J.,
Ebel David L.,
De Smet Marina,
Haesen Rita,
Larson Patrick J.,
Ko Amy,
Verbesselt Rene,
Hunt Thomas L.,
Lins Robert,
Lens Simone,
Porras Arturo G.,
Dieck John,
Keymeulen Bart,
Gertz Barry J.
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.112244
Subject(s) - warfarin , rofecoxib , pharmacokinetics , medicine , pharmacodynamics , crossover study , placebo , anesthesia , anticoagulant , prothrombin time , pharmacology , atrial fibrillation , chemistry , biochemistry , alternative medicine , pathology , cyclooxygenase , enzyme
Objective The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin. Methods Two single‐dose (12.5 or 50 mg of rofecoxib with 25 mg or 30 mg of oral warfarin, respectively, on day 7 of each period) trials (N = 12 men) and 1 steady‐state warfarin trial (25 mg rofecoxib; N = 15, 13 men and 2 women) were completed as two‐period, randomized, balanced, crossover, double‐blind designs. The prothrombin time international normalized ratio (INR) and S(–) and R(+) warfarin enantiomers were assessed during 144 hours after the single warfarin doses. In the steady‐state warfarin trial, after the attainment of a stable INR (1.4–1.7), the stable warfarin dose was co‐administered with rofecoxib (25 mg) and placebo over two 21‐day periods. After the dose of warfarin on day 21, INR and S(–) and R(+) warfarin were assessed during 24 hours. Results Compared with placebo, rofecoxib slightly increased the INR by approximately 5% (90% confidence interval on the geometric ratio, 1.03, 1.08) and 11% (1.04, 1.19) for the two single‐dose warfarin trials with 12.5 and 50 mg of rofecoxib, respectively. In the steady‐state warfarin study with 25 mg of rofecoxib, the INR was increased by 8% (1.02, 1.15). Rofecoxib had no significant effect (versus placebo) on the pharmacokinetics of S(–) warfarin. However, in the 3 studies, treatment with 12.5, 25, and 50 mg of rofecoxib was associated with a 27%, 38%, and 40% increase in the area under the plasma concentration‐time curve of the biologically less active R(+) warfarin. Conclusions Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR. The approximately 8% increase in INR at steady state with warfarin co‐administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin. (Clin Pharmacol Ther 2000;68:626–36.) Clinical Pharmacology & Therapeutics (2000) 68 , 626–636; doi: 10.1067/mcp.2000.112244