Phase I dose-escalation study of the safety and pharmacokinetics of XXXX : an endothelin receptor antagonist for @entity263 .

@entity1 @entity263 @entity417 @entity2232 @entity5 @entity11080 @entity4 @entity2490 @entity9469 @entity10 @entity420
PURPOSE: Evidence suggests that @entity2232 and its primary receptor, the ET(A) receptor, may contribute to the progression of prostate and other @entity5 . @entity9469 ( @entity11080 ) is a highly potent, selective ET(A) receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokinetics (PK) in @entity1 with @entity420 , primarily @entity263 . EXPERIMENTAL DESIGN: This 28-day, single-center Phase I trial evaluated the safety and PK of escalating oral @entity9469 doses (2.5-95 mg) given daily (except day 2) to eligible @entity1 >/==" BORDER="0">18 years old with an @entity420 proven resistant to standard therapy. Priority was given to @entity1 with @entity263 . After 28 days, @entity1 without objective signs of @entity5 progression were eligible to continue @entity9469 in an extension study. RESULTS: Thirty-nine @entity1 (30 of whom had @entity263 ) were treated in cohorts of three @entity1 each with escalating @entity9469 doses (2.5, 5, 10, 20, 30, 45, 60, 75, and 95 mg). The most common adverse events were @entity2490 , @entity10 , and peripheral @entity4 . @entity417 consistent with a reversible hemodilution effect was observed. No maximum tolerated dose was found in the dose range studied. @entity9469 PK were characterized by rapid absorption (mean T(max) = 0.9 h), mean +/- SD oral clearance of 24 +/- 15 liters/h, and volume distribution of 726 +/- 477 liters. PK were approximately dose-proportional and time independent across doses. CONCLUSIONS: @entity9469 is well tolerated, with no dose-limiting adverse events observed up to 95 mg. Adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing.
