Etamicastat, a Novel Dopamine ?-Hydroxylase Inhibitor: Tolerability, Pharmacokinetics, and Pharmacodynamics in Patients With Hypertension

Background Etamicastat is a dopamine ?-hydroxylase (D?H) inhibitor currently in clinical development for the treatment of hypertension and heart failure. Objective This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension. Methods This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM). Results The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat Tmaxwas 1 hour postdose, and mean t½was 19 to 28 hours following repeated administration. Etamicastat underwentN-acetylation byN-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine--30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, -11.66 mm Hg [-21.57 to -1.76;P< 0.05]; 100 mg, -14.92 mm Hg [-24.98 to -4.87;P< 0.01]; and 200 mg, -13.62 mm Hg [-22.29 to -3.95;P< 0.01]). Conclusions Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.