Braeckman Rene A, Stirtan William G, Soni Paresh N
Amarin Pharma Inc., 1430 Route 206, Suite 200, Bedminster, NJ, 07921, USA.
Clin Drug Investig. 2014 Jul;34(7):449-56. doi: 10.1007/s40261-014-0194-1.
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 (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)).
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.
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.
二十碳五烯酸乙酯（IPE）是一种高纯度的二十碳五烯酸（EPA）乙酯处方形式，已被批准用于降低重度（≥5.65 mmol/L）高甘油三酯血症患者的甘油三酯水平。IPE的活性代谢产物EPA主要通过β-氧化代谢，研究表明，像EPA这样的ω-3脂肪酸可能具有抗血栓形成作用。本研究的目的是评估IPE对细胞色素P450 2C9介导代谢的底物华法林的药代动力学和抗凝药效学的影响。
健康成年人在第1天口服华法林（25 mg），在第8 - 35天口服IPE（4 g/天），并在第29天联合给药。主要药代动力学终点是R-和S-华法林从零到无穷大的浓度-时间曲线下面积（AUC(0-∞)）和最大血浆浓度（C(max)）；药效学终点是华法林给药后国际标准化比值（INR）效应-时间曲线下面积（AUC(INR)）和最大INR（INR(max)）。
25名受试者完成了研究。华法林与IPE联合给药组和不联合给药组相比，R-和S-华法林的AUC(0-∞)和C max几何均值比均在0.80 - 1.25的90%置信区间内。AUC(INR)、INR(max)及其比值也相似。
当以25 mg消旋华法林联合给药时，每天4 g的IPE不会显著改变R-和S-华法林的单剂量AUC(0-∞)或C(max)，也不会改变华法林的抗凝药效学。在这项健康成年受试者研究中，联合使用这些药物是安全且耐受性良好的。
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