Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH). Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5–453), a new DβH inhibitor, following repeated dosing. Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days. Results: Etamicastat underwent N-acetylation to its metabolite BIA 5–961. Etamicastat and BIA 5–961 maximum concentrations were achieved at 1–3 and 2–4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5–961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5–961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3–1.9 for etamicastat and 1.3–1.6 for BIA 5–961. Approximately 40%of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5–961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters. Conclusion: Etamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat. Trial Registration: EudraCT No. 2007-004142-33