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.
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–∞) 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).
Twenty-five subjects completed the study. AUC0–∞ 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.
IPE 4 g/day did not significantly change the single-dose AUC0–∞ 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.
KeywordsWarfarin International Normalize Ratio Ezetimibe Racemic Warfarin International Sensitivity Index
This study was designed and sponsored by Amarin Pharma Inc., Bedminster, NJ, USA. Drs. Braeckman and Soni are former employees of Amarin Pharma Inc., Bedminster, NJ, USA, and were employed by Amarin Pharma Inc. during the planning, execution, and manuscript preparation of this study. Medical writing assistance was provided by Beth Daro-Kaftan, PhD, of Peloton Advantage, LLC, Parsippany, NJ, USA, and funded by Amarin Pharma Inc.
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