Cyclosporin increases the exposure to tezosentan, an intravenous dual endothelin receptor antagonist.

OBJECTIVE: To investigate in 12 healthy subjects the pharmacokinetics and tolerability of tezosentan, an endothelin receptor antagonist, when given concomitantly with cyclosporin. METHODS: Tezosentan was infused at a dose of 6.25 mg/h and 25 mg/h for 6 h either alone or following a single dose of 400 mg cyclosporin. Blood and urine samples were collected for pharmacokinetic determinations. Vital signs, electrocardiogram, adverse events, and clinical laboratory parameters were monitored to assess tolerability. RESULTS: Concomitant cyclosporin resulted in a fourfold increase in the exposure to tezosentan. Tezosentan alone was well tolerated. In combination with cyclosporin, and at both doses, all subjects reported headache, hot flushes and nausea/vomiting, some of which were of severe intensity. CONCLUSION: The poor tolerability of the combination of cyclosporin and tezosentan is not correlated with the plasma concentrations of tezosentan.