Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, Allschwil, Switzerland.
Br J Clin Pharmacol. 2011 Jan;71(1):52-60. doi: 10.1111/j.1365-2125.2010.03804.x.
Clazosentan is a selective endothelin A receptor antagonist, formulated for parenteral use, which is in clinical development for the treatment of aneurysmal subarachnoid haemorrhage. The human ADME study showed that most of clazosentan is excreted via the biliary route. The pharmacokinetics (PK) of clazosentan are similar in healthy subjects and those with severe renal impairment.
The results of the present study showed that there was an increase in the exposure to clazosentan with increasing severity of liver impairment. Changes in PK in subjects with mild liver impairment compared with healthy subjects are unlikely to be clinically relevant. There are significant differences in the PK parameters of clazosentan in subjects with moderate and severe liver impairment compared with healthy subjects. The results of this study will allow confident dosing of clazosentan in individuals with moderate and severe liver impairment. AIM To investigate the effect of mild, moderate and severe liver impairment on the pharmacokinetics (PK), tolerability and safety of clazosentan, an intravenous endothelin receptor antagonist.
Healthy subjects with normal liver function (n= 8), subjects with mild (Child Pugh A, n= 8), and with moderate (Child-Pugh B, n= 8) liver impairment received a continuous intravenous infusion of 1 mg h(-1) and subjects with severe liver impairment (Child Pugh C, n= 8) received a continuous intravenous infusion of 0.5 mg h(-1) clazosentan for a duration of 6 h. The pharmacokinetic (PK) parameters of clazosentan were determined by both model-independent and model-dependent methods.
Mean plasma concentrations of clazosentan increased with increasing severity of liver impairment. Geometric means of area under the plasma concentration-time curve from 0 to infinity (AUC((0,∞)) ) were 1.41- (90% CI 1.04, 1.90), 2.37- (90% CI 1.75, 3.19), and 3.79- (90% CI 2.81, 5.11) fold higher in subjects with mild, moderate and severe liver impairment, respectively, compared with healthy subjects. Similar results were obtained by non-compartmental and two-compartmental analysis. A significant positive correlation between clazosentan AUC((0,∞)) and Child-Pugh score (r= 0.83), bilirubin (r= 0.78) and prothrombin time (r= 0.62), and a significant negative correlation with albumin concentrationl (r= 0.71) was observed. Administration of clazosentan was well tolerated in all groups.
The increase in exposure to clazosentan in Child-Pugh A patients is not expected to be clinically relevant and no dose adjustment for these patients is proposed. It is recommended to reduce the dose of clazosentan to half in Child-Pugh B and to one fourth in Child-Pugh C patients.
Clazosentan 是一种选择性内皮素 A 受体拮抗剂，配制用于肠外使用，目前正处于临床试验阶段，用于治疗蛛网膜下腔出血后的动脉瘤。人体 ADME 研究表明，Clazosentan 主要通过胆汁途径排泄。Clazosentan 的药代动力学（PK）在健康受试者和严重肾功能损害患者中相似。
本研究结果表明，随着肝损伤严重程度的增加，Clazosentan 的暴露量增加。与健康受试者相比，轻度肝损伤患者的 PK 变化不太可能具有临床相关性。与健康受试者相比，中度和重度肝损伤患者的 Clazosentan PK 参数存在显著差异。本研究的结果将允许在中度和重度肝损伤患者中自信地给予 Clazosentan 剂量。
研究轻度、中度和重度肝损伤对静脉内内皮素受体拮抗剂 Clazosentan 的药代动力学（PK）、耐受性和安全性的影响。
8 名肝功能正常的健康受试者（n=8）、8 名轻度（Child Pugh A，n=8）和 8 名中度（Child-Pugh B，n=8）肝损伤患者接受持续静脉输注 1mg h(-1)，8 名重度肝损伤患者（Child Pugh C，n=8）接受持续静脉输注 0.5mg h(-1) Clazosentan 6 小时。通过非模型依赖和模型依赖方法确定 Clazosentan 的药代动力学（PK）参数。
Clazosentan 的平均血浆浓度随肝损伤严重程度的增加而增加。与健康受试者相比，轻度、中度和重度肝损伤患者的 Clazosentan 曲线下面积（AUC((0,∞))）的几何平均值分别高出 1.41-（90%CI 1.04, 1.90）、2.37-（90%CI 1.75, 3.19）和 3.79-（90%CI 2.81, 5.11）倍。非房室分析和两房室分析均得到了类似的结果。Clazosentan AUC((0,∞)) 与 Child-Pugh 评分（r=0.83）、胆红素（r=0.78）和凝血酶原时间（r=0.62）呈显著正相关，与白蛋白浓度（r=0.71）呈显著负相关。所有组中 Clazosentan 的给药均耐受良好。
Child-Pugh A 患者中 Clazosentan 暴露量的增加预计不会具有临床相关性，不建议对这些患者进行剂量调整。建议将 Child-Pugh B 患者的 Clazosentan 剂量减少一半，将 Child-Pugh C 患者的剂量减少四分之一。
