van Giersbergen Paul L M, Dingemanse Jasper
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 18, 4123 Allschwil, Switzerland.
Eur J Clin Pharmacol. 2007 Feb;63(2):151-8. doi: 10.1007/s00228-006-0117-z. Epub 2006 Apr 25.
The purpose of this study was to investigate in healthy male subjects the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of clazosentan, an intravenous endothelin receptor antagonist.
Clazosentan was infused at doses of 3-60 mg/h for 3 h, 60 mg/h for 6 h and at 30 mg/h for 12 h. Each dose was given to a separate group of subjects, six of whom received clazosentan and two placebo. Vital signs, ECG, adverse events, and clinical laboratory variables were monitored to assess tolerability. Blood and urine samples were collected frequently for pharmacokinetic and pharmacodynamic determinations.
Infusion of clazosentan up to doses of 30 mg/h for 3 h was well tolerated. A dose of 60 mg/h and longer infusions were less well tolerated and three subjects did not complete the 12-h infusion of 30 mg/h due to adverse events. Headache was the most commonly reported adverse event followed by nausea, vomiting, and nasal congestion. The pharmacokinetics of clazosentan were dose proportional in the dose range investigated. Values (mean and 95% confidence intervals) for clearance and volume of distribution at a dose of 10 mg/h for 3 h were 42.2 (36.6, 48.7) l/h and 32.4 (27.0, 38.8) l, respectively. Both variables were independent of dose. The elimination of clazosentan was characterized by a very rapid disposition phase with a half-life of 6-10 min. Compared to baseline, endothelin-1 concentrations increased approximately 2-fold after infusion of clazosentan but no dose-dependent relationship could be discerned for this effect.
The observed tolerability, pharmacokinetic, and pharmacodynamic profile warrant further clinical development of clazosentan at lower doses.
本研究旨在调查健康男性受试者对静脉注射内皮素受体拮抗剂克拉生坦递增剂量的耐受性、药代动力学和药效学。
克拉生坦以3 - 60mg/h的剂量输注3小时，60mg/h的剂量输注6小时，30mg/h的剂量输注12小时。每个剂量给予单独一组受试者，其中6人接受克拉生坦，2人接受安慰剂。监测生命体征、心电图、不良事件和临床实验室指标以评估耐受性。频繁采集血样和尿样进行药代动力学和药效学测定。
输注剂量达30mg/h持续3小时的克拉生坦耐受性良好。60mg/h的剂量及更长时间的输注耐受性较差，3名受试者因不良事件未完成30mg/h的12小时输注。头痛是最常报告的不良事件，其次是恶心、呕吐和鼻塞。在所研究的剂量范围内，克拉生坦的药代动力学呈剂量正比关系。剂量为10mg/h持续3小时时，清除率和分布容积的值（均值和95%置信区间）分别为42.2(36.6, 48.7)l/h和32.4(27.0, 38.8)l，两个变量均与剂量无关。克拉生坦的消除以非常快速的处置相为特征，半衰期为6 - 10分钟。与基线相比，输注克拉生坦后内皮素-1浓度增加约2倍，但该效应未发现剂量依赖关系。
观察到的耐受性以及药代动力学和药效学特征表明，克拉生坦在较低剂量下值得进一步开展临床研究。
