Entry-into-humans study with tezosentan, an intravenous dual endothelin receptor antagonist

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.