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.


CONCLUSIONS
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.
van Giersbergen
Paul L M
PL
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Dingemanse
Jasper
J
D000328:Adult; D004146:Dioxanes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D012737:Sex Factors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan