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首页> 外文期刊>Clinical drug investigation >Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects
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Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects

机译：Macitentan对健康男性华法林药代动力学和药效学影响的研究

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Background and Objectives: Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects. Methods: This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed. Results: Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without macitentan. Conclusions: The absence of effect of macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.
机译：背景与目的：Macitentan是一种新型的双重内皮素受体拮抗剂，最近被批准用于治疗肺动脉高压（PAH）。华法林是常用于PAH患者的抗凝剂，其治疗指数狭窄，并易于与药物发生潜在的相互作用。这项研究评估了Macitentan对健康受试者单剂量华法林的药代动力学和药效学的影响。方法：这是一项针对14位健康男性受试者的随机，开放标签，单中心，双向交叉（治疗A，然后治疗B，反之亦然）的I期研究。治疗A在第1天的负荷量为macitentan 30 mg，然后每天10 mg，共8天，在第4天给予单剂量的25 mg华法林。治疗B在第1天为单剂量的华法林。评估华法林药代动力学（R和S-华法林）和药效学[国际标准化比率（INR）和VII因子]。还评估了Macitentan及其活性代谢物的血浆谷浓度（ACT-132577）以及每种治疗的安全性和耐受性。结果：在两个治疗期间，R-和S-华法林的血浆浓度相似。华法林不影响macitentan或ACT-132577的平均谷底血浆浓度。 Macitentan不会影响华法林的药效。有和没有macitentan时，平均INR和VII因子活性相对于时间的分布情况相似。结论：Macitentan对单剂量华法林的药代动力学和药效学没有影响，这表明两种药物可以同时给药而无需调整剂量。

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