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.


CONCLUSIONS
The poor tolerability of the combination of cyclosporin and tezosentan is not correlated with the plasma concentrations of tezosentan.
van Giersbergen
Paul L M
PL
Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 18, 4123 Allschwil, Switzerland. paul.vangiersbergen@actelion.com
Bodin
Frédéric
F
Dingemanse
Jasper
J
D019540:Area Under Curve; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics*
D065128:Endothelin Receptor Antagonists; D007166:Immunosuppressive Agents; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan; D016572:Cyclosporine