Entry-into-humans study with tezosentan, an intravenous dual endothelin receptor
antagonist.
Author(s): Dingemanse J(1), Clozel M, van Giersbergen PL.
Affiliation(s): Author information:
(1)Actelion Pharmaceuticals Ltd, Department of Preclinical Pharmacology,
Allschwil, Switzerland. jasper.dingemanse@actelion.com
Publication date & source: 2002, J Cardiovasc Pharmacol. , 39(6):795-802
The purpose of this study was to investigate the tolerability, pharmacokinetics,
and pharmacodynamics of ascending doses of tezosentan, an IV dual endothelin
receptor antagonist, during first administration in humans. Tezosentan infused at
doses of 5, 20, 50, 100, 200, 400, and 600 mg for 1 h was administered to
sequential groups of six male subjects in a randomized, placebo-controlled,
double-blind design. Recording of vital signs, electrocardiogram, adverse events,
and clinical laboratory parameters monitored tolerability and safety. Blood
samples were collected frequently for pharmacokinetic determinations and
measurement of plasma endothelin-1 concentrations. Tezosentan was well tolerated
at all dose levels. Headache was the most frequently reported adverse event and
occurred at a higher incidence than with placebo at doses of > or = 100 mg. No
clinically relevant changes in vital signs, electrocardiographic, or clinical
laboratory parameters occurred. Plasma concentrations of tezosentan rapidly
approached steady state and could be described by a two-compartment model. The
volume of distribution at steady state (approximately 16 l) and the clearance
(approximately 30 l/h) were considered independent of dose, in view of the wide
dose range explored. A pronounced and rapid disposition phase (half-life 6 min),
accounting for the major part of the elimination, was followed by a slower phase
(half-life 3 h), probably caused by distribution from tissues. Endothelin-1
concentrations increased in a dose- and concentration-dependent fashion and
returned slowly to baseline after termination of the infusion. Tezosentan
warrants further clinical development in view of its tolerability and
pharmacokinetic profile, which appears advantageous for application in emergency
situations.
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