Dingemanse Jasper, Clozel Martine, van Giersbergen Paul L M
Actelion Pharmaceuticals Ltd, Department of Preclinical Pharmacology, Allschwil, Switzerland.
J Cardiovasc Pharmacol. 2002 Jun;39(6):795-802. doi: 10.1097/00005344-200206000-00004.
The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of tezosentan, an IV dual endothelin receptor antagonist, during first administration in humans. Tezosentan infused at doses of 5, 20, 50, 100, 200, 400, and 600 mg for 1 h was administered to sequential groups of six male subjects in a randomized, placebo-controlled, double-blind design. Recording of vital signs, electrocardiogram, adverse events, and clinical laboratory parameters monitored tolerability and safety. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations. Tezosentan was well tolerated at all dose levels. Headache was the most frequently reported adverse event and occurred at a higher incidence than with placebo at doses of > or = 100 mg. No clinically relevant changes in vital signs, electrocardiographic, or clinical laboratory parameters occurred. Plasma concentrations of tezosentan rapidly approached steady state and could be described by a two-compartment model. The volume of distribution at steady state (approximately 16 l) and the clearance (approximately 30 l/h) were considered independent of dose, in view of the wide dose range explored. A pronounced and rapid disposition phase (half-life 6 min), accounting for the major part of the elimination, was followed by a slower phase (half-life 3 h), probably caused by distribution from tissues. Endothelin-1 concentrations increased in a dose- and concentration-dependent fashion and returned slowly to baseline after termination of the infusion. Tezosentan warrants further clinical development in view of its tolerability and pharmacokinetic profile, which appears advantageous for application in emergency situations.
本研究的目的是在首次人体给药期间，研究静脉注射双重内皮素受体拮抗剂替唑生坦递增剂量的耐受性、药代动力学和药效学。在一项随机、安慰剂对照、双盲设计中，将6名男性受试者依次分为不同组，分别静脉输注剂量为5、20、50、100、200、400和600mg的替唑生坦，持续1小时。记录生命体征、心电图、不良事件和临床实验室参数以监测耐受性和安全性。频繁采集血样用于药代动力学测定和血浆内皮素-1浓度的测量。替唑生坦在所有剂量水平下耐受性良好。头痛是最常报告的不良事件，在剂量≥100mg时，其发生率高于安慰剂组。生命体征、心电图或临床实验室参数未出现临床相关变化。替唑生坦的血浆浓度迅速接近稳态，可用二室模型描述。鉴于所研究的剂量范围较宽，稳态分布容积（约16L）和清除率（约30L/h）被认为与剂量无关。消除的主要部分是一个明显且快速的处置相（半衰期6分钟），随后是一个较慢的相（半衰期3小时），可能是由组织分布引起的。内皮素-1浓度呈剂量和浓度依赖性增加，输注结束后缓慢恢复至基线。鉴于替唑生坦的耐受性和药代动力学特征，其在紧急情况下应用似乎具有优势，值得进一步开展临床研究。
