Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetic and anticoagulation parameters.
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.
Amarin Pharma Inc., 1430 Route 206, Suite 200, Bedminster, NJ, 07921, USA.
Rene A
RA
Braeckman
William G
WG
Stirtan
Paresh N
PN
Soni
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D000925:Anticoagulants; D014859:Warfarin; C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid; D065729:Cytochrome P-450 CYP2C9