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

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Almeida, L (Author) Other; Nunes, T (Author) Other; Costa, R (Author) Other; Rocha, JF (Author) Other; Vaz Da Silva, M (Author) FMUP; soares-da-silva, p (Author) FMUP

Journal

Title: Clinical Therapeutics

Vol. 35

Pages: 1983-1996

ISSN: 0149-2918

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 25 Citations

Scopus - 26 Citations

Other information

Authenticus ID: P-008-JPE

DOI: 10.1016/j.clinthera.2013.10.012

Abstract (EN): Background: Etamicastat is a dopamine beta-hydroxylase (DPH) 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 SO, 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 T-max was 1 hour post-dose, and mean t(1/2) was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUG 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14