title: Cardiovascular safety pharmacology profile of etamicastat, a novel peripheral selective dopamine-β-hydroxylase inhibitor.
abstract: Etamicastat, a peripheral reversible dopamine-β-hydroxylase inhibitor, blocked the hERG current amplitude with an IC50 value of 44.0µg/ml in HEK 293 cells. At 0.3 and 3µg/ml, etamicastat had no effects on the action potential (AP) in male dog Purkinje fibers. At 30µg/ml, etamicastat significantly affected resting membrane potential (+4%), AP amplitude (-4%), AP duration at 60% (-14%) and AP duration at 90% (+5%) repolarization, and AP triangulation (+79%). In the telemetered conscious male dog, etamicastat (up to 20mg/kg) had no effects on arterial blood pressure, heart rate and the PR interval. At 10 and 20mg/kg, the QTc interval was slightly prolonged (8-9% max, P<0.05). No arrhythmia or other changes in the morphology of the ECG were observed. The maximum observed plasma concentrations (Cmax) of etamicastat (i.e. 3h post-administration) were 1.4 and 3.7µg/ml at 10 and 20mg/kg, respectively. No deleterious effects, including ECG disturbance were observed in male and female dogs dosed by gavage with etamicastat (up to 20mg/kg/day) for 28 days. Mean plasma Cmax etamicastat levels ranged between 2.4 and 6.3µg/ml on Day 1 and Day 28 of treatment, respectively. It is concluded that the blockade of the delayed rectifier potassium channels by etamicastat together with the QTc interval prolongation observed in conscious dogs can be considered as modest with respect to the measured plasmatic concentrations. These findings suggest that etamicastat is not likely to prolong the QT interval at therapeutic doses (~0.2µg/ml).
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457 S. Mamede do Coronado, Portugal.
authors: Nuno Miguel
authors: NM
authors: Pires
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457 S. Mamede do Coronado, Portugal.
authors: Ana Isabel
authors: AI
authors: Loureiro
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457 S. Mamede do Coronado, Portugal.
authors: Bruno
authors: B
authors: Igreja
authors: Pierre Lacroix Consultant, 3 rue Théodore Botrel, 35830 Betton, France.
authors: Pierre
authors: P
authors: Lacroix
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457 S. Mamede do Coronado, Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors: Patrício
authors: P
authors: Soares-da-Silva
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004285:Dogs; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D012449:Safety; D013686:Telemetry
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase
keywords: AP repolarization; Cardiac risk assessment; Etamicastat; Purkinje fiber; QT prolongation