Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans

Aims Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA select ive receptor antagonist ABT-627 in healthy humans. Methods Healthy volunteers were included in two studies with cross-over des ign. Subjects received single or multiple dose (an 8 day period) administra tion of oral ABT-627 or matched placebo, in a dose range of 0.2-40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haem odynamics under resting conditions and on forearm vasoconstriction in respo nse to ET-1 were assessed. Results ABT-627 was generally well tolerated in both studies, with transien t headache being the most reported adverse event (in 62% vs 4% during place bo, P < 0.05, for Study 1 and in 42% vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at approximate to 1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treat ment, at a dose level of 5 mg and above, also effectively blocked forearm v asoconstriction to ET-1. ABT-627 caused a significant reduction in peripher al resistance as compared with placebo (16 +/- 1 vs 19 +/- 1, 18 +/- 2 vs 2 3 +/- 3, 15 +/- 1 vs 17 +/- 1 AU at 1, 5, 20 mg in Study 2) with only a mil d decrease in blood pressure (79 +/- 2 vs 84 +/- 3, 80 +/- 4 vs 90 +/- 5, 7 5 +/- 3 vs 79 +/- 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate d ose-dependent increase in circulating immunoreactive ET levels (a maximal i ncrease of 50% over baseline at the 20 mg dose level). Conclusions The oral ETA receptor blocker ABT-627 is well tolerated, rapidl y absorbed, effectively blocks ET-1 induced vasoconstriction and causes a d ecrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease.