Effect of Gender on the Tolerability, Safety and Pharmacokinetics of Clazosentan Following Long-Term Infusion

Authors: van Giersbergen, Paul L.M.; Dingemanse, Jasper

Source: Clinical Drug Investigation, Volume 27, Number 11, 2007 , pp. 797-802(6)

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Abstract:

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.

Keywords: Clazosentan; Endothelin A receptor antagonists; Gender differences

Document Type: Research article

Affiliations: 1: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

Publication date: 2007-01-01