Dingemanse Jasper, Gunawardena Kulasiri A, van Giersbergen Paul L M
Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
Br J Clin Pharmacol. 2006 Apr;61(4):405-13. doi: 10.1111/j.1365-2125.2006.02586.x.
To investigate the pharmacokinetics, pharmacodynamics and tolerability of the dual endothelin receptor antagonist tezosentan in caucasian and Japanese subjects.
Twelve subjects of each ethnic origin were treated in a double-blind, randomized design with sequential 3-h infusions of 2.5, 5.0, 12.5 and 25 mg h(-1), or placebo. Vital signs, ECG and adverse events were recorded and blood samples collected for determination of plasma concentrations of tezosentan and endothelin-1 (ET-1).
Tezosentan was well tolerated in both ethnic groups with no clinically significant differences in laboratory measurements, ECG parameters and vital signs. The plasma concentration-time profiles of tezosentan were described by a three-compartment model with half-lives of approximately 5 min, 41 min and 3.6 h. Mean clearance and volume of distribution were approximately 35 l h(-1) and 20 l, respectively. Differences in the means (95% confidence intervals) between ethnic groups in these two parameters were 6.0 l h(-1) (-1.3, 13.3) and 4.3 l (-1.3, 9.9), respectively. Baseline ET-1 concentrations were similar but increases in response to tezosentan were greater in caucasian than in Japanese subjects. An indirect response model described the relationship between tezosentan and ET-1 plasma concentrations. The mean concentrations inhibiting 50% of ET-1 clearance (IC(50)) in caucasian and Japanese subjects were 243 and 227 ng ml(-1), respectively, with a difference in the means of 28.6 ng ml(-1) (-52.7, 110).
The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan.
研究双重内皮素受体拮抗剂替唑生坦在白种人和日本受试者中的药代动力学、药效学及耐受性。
采用双盲、随机设计，对每个种族的12名受试者依次进行3小时输注2.5、5.0、12.5和25 mg h⁻¹的替唑生坦或安慰剂治疗。记录生命体征、心电图和不良事件，并采集血样以测定替唑生坦和内皮素-1（ET-1）的血浆浓度。
两个种族的受试者对替唑生坦耐受性均良好，实验室检查、心电图参数和生命体征方面均无临床显著差异。替唑生坦的血浆浓度-时间曲线可用三室模型描述，半衰期约为5分钟、41分钟和3.6小时。平均清除率和分布容积分别约为35 l h⁻¹和20 l。两个种族在这两个参数上的均值差异（95%置信区间）分别为6.0 l h⁻¹（-1.3, 13.3）和4.3 l（-1.3, 9.9）。基线ET-1浓度相似，但白种人受试者对替唑生坦的反应性升高幅度大于日本受试者。间接反应模型描述了替唑生坦与ET-1血浆浓度之间的关系。白种人和日本受试者中抑制50% ET-1清除率（IC₅₀）的平均浓度分别为243和227 ng ml⁻¹，均值差异为28.6 ng ml⁻¹（-52.7, 110）。
健康受试者的数据表明，白种人和日本患者可用相似的替唑生坦给药方案治疗。
