Effect of gender on the tolerability, safety and pharmacokinetics of clazosentan following long-term infusion

Objective: The purpose of this study was to investigate the effect of gender on the tolerability, safety and pharmacokinetics of clazosentan, an intravenous endothelin receptor antagonist. Methods: Clazosentan was infused at a dosage of 0.05 mg/kg/h or 0. 1 mg/kg/h for 72 hours in 8 female and 8 male healthy volunteers, respectively. Tolerability and safety were assessed via the recording of dose reductions/infusion stops, vital signs, ECG, adverse events and clinical laboratory variables. Blood samples were collected for the determination of clazosentan and endothelin-1 concentrations. Results: The occurrence of adverse events such as headache, vomiting and nausea of moderate to severe intensity led either to discontinuation of the infusion or to a dose reduction in the majority of volunteers. The values (mean and 95% confidence intervals) for clearance were 37.7 (32.8, 43.4) and 35.2 (27.8, 44.5) L/h in male and female volunteers, respectively. Conclusion: Long-term infusion of clazosentan at the doses tested was poorly tolerated in both male and female volunteers. Gender appeared to have no influence on the pharmacokinetics of clazosentan.