Bruderer Shirin, Okubo Kaori, Mukai Hideya, Mant Tim, Dingemanse Jasper
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Nippon Shinyaku Co. Ltd., Kyoto, Japan.
Clin Ther. 2016 May;38(5):1228-1236.e1. doi: 10.1016/j.clinthera.2016.03.014. Epub 2016 Apr 8.
Selexipag is a new orally available nonprostanoid prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Warfarin is commonly used in patients with pulmonary arterial hypertension. Possible pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy individuals were investigated.
This was a double-blind, 2-way, 2-treatment crossover, Phase I study. Nineteen healthy men received a single dose of selexipag 400 μg or placebo on day 1, followed by selexipag 400 μg or placebo BID on days 2 to 12. A concomitant single dose of warfarin 20 mg was administered in the morning of day 8.
Both treatments were well tolerated. The most frequently reported adverse event was headache in both treatments. Geometric mean ratios and 90% CIs of the maximum international normalized ratio (geometric mean ratio = 0.96; 90% CI, 0.90-1.03) and international normalized ratio AUC0-144h (geometric mean ratio = 0.98; 90% CI, 0.96-1.00)] during treatment with warfarin and selexipag versus treatment with only warfarin were inside the reference limits of 0.80 to 1.25. The 90% CIs of the geometric mean ratios of AUC and Cmax for R- and S-warfarin during treatment with warfarin and selexipag versus treatment with warfarin alone were inside the reference range of 0.80 to 1.25. After repeated-dose administration of 400 μg selexipag, the AUC of selexipag and its active metabolite, ACT-333679, at steady state were not affected by a single dose of 20 mg warfarin.
Steady-state levels of selexipag and ACT-333679 after repeated doses of 400 μg selexipag had no influence on the warfarin pharmacodynamic variables. There was no pharmacokinetic interaction between selexipag and warfarin.
司来帕格是一种新型口服非前列腺素类前列环素受体激动剂，用于治疗肺动脉高压。华法林常用于肺动脉高压患者。本研究调查了健康个体中司来帕格与华法林之间可能存在的药效学和药代动力学相互作用。
这是一项双盲、双向、双治疗交叉的I期研究。19名健康男性在第1天接受单剂量400μg司来帕格或安慰剂，随后在第2至12天接受司来帕格400μg或安慰剂每日两次给药。在第8天上午同时给予单剂量20mg华法林。
两种治疗耐受性均良好。两种治疗中最常报告的不良事件均为头痛。与仅使用华法林治疗相比，在华法林和司来帕格联合治疗期间，国际标准化比值最大值的几何平均比值及90%可信区间（几何平均比值=0.96；90%可信区间，0.90 - 1.03）以及国际标准化比值AUC0 - 144h（几何平均比值=0.98；90%可信区间，0.96 - 1.00）均在0.80至1.25的参考范围内。与单独使用华法林治疗相比，在华法林和司来帕格联合治疗期间，R - 和S - 华法林的AUC和Cmax几何平均比值的90%可信区间在0.80至1.25的参考范围内。在重复给予400μg司来帕格后，单剂量20mg华法林未影响司来帕格及其活性代谢产物ACT - 333679在稳态时的AUC。
重复给予400μg司来帕格后的稳态水平对华法林药效学变量无影响。司来帕格与华法林之间不存在药代动力学相互作用。
