Effect of Food on the Pharmacokinetic Profile of Etamicastat (BIA 5-453)

Abstract

Background: Etamicastat is a novel, potent, and reversible peripheral dopamineb-hydroxylase inhibitor that has been administered orally at doses up to 600 mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200 mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC last ), and AUC from time zero to infinity (AUC ¥ ). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125).

Cardiovascular safety pharmacology profile of etamicastat, a novel peripheral selective dopamine-ß-hydroxylase inhibitor

“…Recent studies indicate that the major metabolic pathway of etamicastat in humans is concerned with its N-acetylation to BIA 5-961, mainly by NAT2 (Nunes et al, , , 2010Rocha et al, 2012;Vaz-da-Silva et al, 2011), which has been described to be responsible for interspecies variability in drug metabolism (Gao et al, 2006;Glinsukon et al, 1975;Sharer et al, 1995). In line with these findings is the observation that dogs, unlike humans, totally lack the enzyme family arylamine N-acetyltransferases (Collins, 2001), which may explain the significant higher exposure to etamicastat observed in the dog, in comparison with humans, and the finding that no Nacetylation of etamicastat to BIA 5-961 was observed.…”