Phase 1 Study of the Effect of Icosapent Ethyl on Warfarin Pharmacokinetic and Anticoagulation Parameters

Background and Objective Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved to reduce triglyceride levels in patients with severe (≥5.65 mmol/L) hypertriglyceridemia. EPA, the active metabolite of IPE, is mainly metabolized via β-oxidation, and studies suggest that omega-3 fatty acids such as EPA may have antithrombotic effects. The objective of this study was to evaluate the effect of IPE on the pharmacokinetic and anticoagulation pharmacodynamics of warfarin, a substrate of cytochrome P450 2C9-mediated metabolism. Methods Healthy adults received oral warfarin (25 mg) on day 1, oral IPE (4 g/day) on days 8–35, and co-administration on Day 29. Primary pharmacokinetic end points were area under the concentration-versus-time curve from zero to infinity (AUC 0–∞ ) and maximum plasma concentration ( C max ) for R- and S- warfarin; pharmacodynamic end points were area under the international normalized ratio (INR) effect-time curve after the warfarin dose (AUC INR ) and maximum INR (INR max ). Results Twenty-five subjects completed the study. AUC 0–∞ and C max ratios of geometric means for both R- and S- warfarin following co-administration of warfarin with versus without IPE were within the 90 % confidence intervals of 0.80–1.25. AUC INR , INR max , and ratios were also similar. Conclusions IPE 4 g/day did not significantly change the single-dose AUC 0–∞ or C max of R - and S -warfarin or the anticoagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. Co-administration of these drugs was safe and well tolerated in this study of healthy adult subjects.