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

Abstract

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 selective receptor antagonist ABT‐627 in healthy humans. Methods Healthy volunteers were included in two studies with cross‐over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT‐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 haemodynamics under resting conditions and on forearm vasoconstriction in response to ET‐1 were assessed. Results ABT‐627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62% vs 4% during placebo, 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 ≈ 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 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET‐1. ABT‐627 caused a significant reduction in peripheral resistance as compared with placebo (16 ± 1 vs 19 ± 1, 18 ± 2 vs 23 ± 3, 15 ± 1 vs 17 ± 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 ± 2 vs 84 ± 3, 80 ± 4 vs 90 ± 5, 75 ± 3 vs 79 ± 1 at 1, 5, 20 mg in Study 2). ABT‐627 caused a moderate dose‐dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level). Conclusions The oral ETA receptor blocker ABT‐627 is well tolerated, rapidly absorbed, effectively blocks ET‐1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT‐627 may be a valuable tool in treatment of cardiovascular disease.