Tolerability, pharmacokinetics, and pharmacodynamics of clazosentan, a parenteral endothelin receptor antagonist.
OBJECTIVE
The purpose of this study was to investigate in healthy male subjects the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of clazosentan, an intravenous endothelin receptor antagonist.


METHODS
Clazosentan was infused at doses of 3-60 mg/h for 3 h, 60 mg/h for 6 h and at 30 mg/h for 12 h. Each dose was given to a separate group of subjects, six of whom received clazosentan and two placebo. Vital signs, ECG, adverse events, and clinical laboratory variables were monitored to assess tolerability. Blood and urine samples were collected frequently for pharmacokinetic and pharmacodynamic determinations.


RESULTS
Infusion of clazosentan up to doses of 30 mg/h for 3 h was well tolerated. A dose of 60 mg/h and longer infusions were less well tolerated and three subjects did not complete the 12-h infusion of 30 mg/h due to adverse events. Headache was the most commonly reported adverse event followed by nausea, vomiting, and nasal congestion. The pharmacokinetics of clazosentan were dose proportional in the dose range investigated. Values (mean and 95% confidence intervals) for clearance and volume of distribution at a dose of 10 mg/h for 3 h were 42.2 (36.6, 48.7) l/h and 32.4 (27.0, 38.8) l, respectively. Both variables were independent of dose. The elimination of clazosentan was characterized by a very rapid disposition phase with a half-life of 6-10 min. Compared to baseline, endothelin-1 concentrations increased approximately 2-fold after infusion of clazosentan but no dose-dependent relationship could be discerned for this effect.


CONCLUSIONS
The observed tolerability, pharmacokinetic, and pharmacodynamic profile warrant further clinical development of clazosentan at lower doses.
van Giersbergen
Paul L M
PL
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 18, 4123 Allschwil, Switzerland. paul.vangiersbergen@actelion.com
Dingemanse
Jasper
J
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002853:Chromatography, Liquid; D004146:Dioxanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015508:Nasal Obstruction / Q000139:chemically induced; D009325:Nausea / Q000139:chemically induced; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014839:Vomiting / Q000139:chemically induced
D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan