Divergent effects of raloxifene HCl on the the pharmacokinetics and pharmacodynamics of warfarin

Purpose, Evista (R) (raloxifene HCl) is a nonsteroidal selective estrogen r eceptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. T he potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy postmenopausal women. Methods. Single doses of warfarin (20 mg) were administered prior to and du ring 2 weeks of dosing with raloxifene 120 mg/day. Each warfarin dose was f ollowed by pharmacokinetic sampling and prothrombin time measurements. Results. Raloxifene administration resulted in 7.1% and 14.1% decreases in the clearance (CLP/F) and 7.4% and 9.8% decreases in the volume of distribu tion (V-SS/F) of R- and S-warfarin, respectively (all p less than or equal to 0.05). In contrast to the slightly higher plasma concentrations of R- an d S-warfarin, raloxifene reduced the maximum prothrombin time (PTmax) by 10 % and the area under the PT versus time curve from 0-120 h (AUC(PT)) by 8% (p < 0.01). Conclusions. Raloxifene administration may result in a small increase in sy stemic warfarin exposure that is associated with a diminution, not augmenta tion, of the pharmacodynamic effect. Due to the: small magnitude of this ef fect. concomitant administration of raloxifene and warfarin is not likely t o result in clinically significant drug-drug interaction.