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

Clinical drug investigation

PubMedID: 24760401

Braeckman RA, Stirtan WG, Soni PN. Phase 1 Study of the Effect of Icosapent Ethyl on Warfarin Pharmacokinetic and Anticoagulation Parameters. Clin Drug Investig. 2014;.
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 ß-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 (AUC0-8) 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 (AUCINR) and maximum INR (INRmax).

RESULTS
Twenty-five subjects completed the study. AUC0-8 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. AUCINR, INRmax, and ratios were also similar.

CONCLUSIONS
IPE 4 g/day did not significantly change the single-dose AUC0-8 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.