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首页> 外文期刊>Pharmacology: International Journal of Experimental and Clinical Pharmacology >Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects
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Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

机译：多剂量上滴定研究，评价Selexipag的安全性，耐受性，药代动力学和药效学，一种口服选择性前列环素受体激动剂，在健康受试者中

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Objective: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. Methods: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 mug; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 ug between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Results: Dose levels of selexipag up to 1,600 ug were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curveand the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Conclusions: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct Of future Clinical trials.
机译：目的：本研究的目的是评估Selexipag的安全性，耐受性，药代动力学和药效学，口服可用的选择性前列环素受体激动剂，在健康受试者中肺动脉高血压的开发。方法：这是一种双盲，安慰剂控制，随机的多个上升剂量，上滴定研究。男性受试者接受了每天3天每天两次的口服剂量的Selexipag（400-1,800杯; n = 12）或安慰剂（n = 4），每次剂量水平之间的增量步骤为200μg。收集标准安全性和可耐受性数据。采集血液样品以评估Selexipag及其活性代谢物ACT-333679的药代动力学以及对血小板聚集的可能影响。结果：耐受均匀1,600ug的Selexipag剂量水平耐受良好，并且将该剂量鉴定为最大耐受剂量。 ACT-333679的血浆暴露量比Selexipag高约4倍。每次剂量水平的第3天达到两种化合物的稳态条件，并且未观察到Selexipag或Act-333679的积累。基于曲法下的区域最大血浆浓度，Selexipag和Act-333679的药代动力学剂量成比例。在最高剂量水平处，Selexipag和Act-333679的几何平均终端半衰期分别为1.4和8.7小时。没有明显的药物或剂量依赖性模式，观察到对血小板聚集的影响是可变的。结论：口服施用Selexipag剂量的口服耐受性。目前的结果支持未来的临床试验。

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