title: Etamicastat, a novel dopamine β-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension.
abstract: BACKGROUND
  Etamicastat is a dopamine β-hydroxylase (DβH) 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 Tmax was 1 hour postdose, and mean t½ 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 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.
authors.affiliation: Health Sciences Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S Mamede do Coronado, Porto, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S Mamede do Coronado, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Costa
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S Mamede do Coronado, Porto, Portugal.
authors.forename: José F
authors.initials: JF
authors.lastname: Rocha
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S Mamede do Coronado, Porto, Portugal; Department of Cardiology, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vaz-da-Silva
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S Mamede do Coronado, Porto, Portugal; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D007093:Imidazoles; D007527:Isoenzymes; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human
keywords: ambulatory blood pressure monitoring; dopamine β-hydroxylase inhibitors; etamicastat; hypertension; pharmacodynamics; pharmacogenomics; pharmacokinetics; tolerability