Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
Eur J Clin Pharmacol. 2011 Oct;67(10):977-84. doi: 10.1007/s00228-011-1043-2. Epub 2011 May 4.
To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin receptor antagonist, in healthy male subjects.
This double-blind, placebo-controlled study was performed in seven groups of eight healthy male subjects. Doses of 0.2, 1, 5, 25, 100, 300 and 600 mg or placebo (two subjects per group) were administered. Plasma macitentan and endothelin-1 and serum total bile salt concentrations were measured and analysed non-compartmentally. Plasma and urine were analysed qualitatively for the presence of metabolites and one of these, ACT-132577, was also measured quantitatively in plasma. Standard tolerability measurements were performed throughout the study.
Macitentan was slowly absorbed and, at a dose of 300 mg, the t(1/2) (95% confidence interval, CI) was 17.5 h (14.1, 21.8). The dose-proportionality coefficient β for C(max) (95% CI) was 0.83 (0.79, 0.87) indicating less than dose-proportional pharmacokinetics of macitentan. In plasma, a pharmacologically active oxidative depropyl metabolite, ACT-132577, was found whereas in urine two minor metabolites were detected. The t(1/2) of ACT-132577 (95% CI) was 65.6 h (53.1, 80.9). Macitentan dose-dependently increased endothelin-1 concentrations up to 2.2-fold (95% CI 1.4, 2.4) at a dose of 600 mg, but had no consistent effect on total bile salts. Macitentan was well tolerated up to and including a dose of 300 mg, the maximum tolerated dose. Headache, nausea and vomiting were dose-limiting adverse events.
The pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.
研究健康男性单次递增剂量麦西替坦（一种内皮素受体拮抗剂）的药代动力学、药效学和耐受性。
这项双盲、安慰剂对照研究在 7 组 8 名健康男性受试者中进行。给予 0.2、1、5、25、100、300 和 600mg 或安慰剂（每组 2 名受试者）。非房室分析测定血浆麦西替坦和内皮素-1及血清总胆汁盐浓度。定性分析血浆和尿液中代谢产物的存在情况，其中一种代谢产物 ACT-132577 也定量测定于血浆中。整个研究过程中进行标准耐受性测量。
麦西替坦吸收缓慢，在 300mg 剂量下，t1/2（95%置信区间，CI）为 17.5 小时（14.1，21.8）。Cmax（95%CI）的剂量比例系数β为 0.83（0.79，0.87），表明麦西替坦的药代动力学呈非比例性。在血浆中发现了一种具有药理活性的氧化去丙基代谢产物 ACT-132577，而在尿液中检测到两种次要代谢产物。ACT-132577 的 t1/2（95%CI）为 65.6 小时（53.1，80.9）。麦西替坦剂量依赖性地增加了内皮素-1 的浓度，最高可达 600mg 时的 2.2 倍（95%CI 1.4，2.4），但对总胆汁盐没有一致的影响。麦西替坦的耐受性良好，最高剂量可达 300mg，即最大耐受剂量。头痛、恶心和呕吐是剂量限制不良事件。
麦西替坦的药代动力学和耐受性特征与每日一次给药方案一致，值得在临床研究中进一步研究。
