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

Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600mg 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 200mg 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). Results: Etamicastat C(max), AUC(last), and AUC(∞) were 229 ng/mL, 1856 • h/mL, and 2238 ng • h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng • h/mL, and 2119 ng • h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for C(max), 93.59% (90% CI 89.28, 98.11) for AUC(last), and 96.47% (90% CI 91.67, 101.53) for AUC(∞). Time to C(max) was prolonged by the presence of food (p < 0.001). The C(max), AUC(last), and AUC(∞) values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng • h/mL, and 2009 ng • h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng • h/mL, and 1677 ng • h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for C(max), 79.41% (90% CI 56.77, 68.63) for AUC(last), and 83.47% (90% CI 76.62, 90.93) for AUC(∞). A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments. Conclusion: Etamicastat was well tolerated. The C(max) of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals.