Safety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to humans

Objective: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BIA 2-093 [S-(-)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/azepine-5-carboxamide] in healthy male volunteers. Design: This was a double-blind, randomised, placebo-controlled, single ascending dose study performed with BIA 2-093, a new putative antiepileptic drug. Participants and methods: Groups of eight healthy male subjects (two randomised to receive placebo and the remaining six to receive BIA 2-093) received single oral doses of BIA 2-093 of 20, 50, 100, 200, 400, 600, 900 and 1200mg. A total of 64 healthy male volunteers aged 18-35 years participated in the study. Results: The incidence of adverse events, which were mild in severity, was similar between all treatment groups, including the placebo group. There were no serious adverse events during this study. No clinically significant abnormalities in laboratory safety tests, vital signs, weight, physical examination or ECG were reported. BIA 2-093 appeared to be rapidly and extensively metabolised to BIA 2-005 [RS(± -10,11-dihydro-10-hydroxy-5H-dibenzo/b,f/azepine-5-carbox-amide], the major metabolite, and oxcarbazepine (the minor metabolite), following single oral doses of BIA 2-093 of 20-1200mg. Plasma BIA 2-093 concentrations were generally below the limit of quantification of the assay. Maximum plasma concentrations (Cmax) of BIA 2-005 and oxcarbazepine were reached, respectively, at 0.75-4h and 6h postdose, after which they declined with an approximate mean apparent terminal half-life of 8-17h and 7-12h, respectively. The increase in systemic exposure to BIA 2-005 was approximately proportional to the administered dose for Cmax and greater than dose proportional for the area under the concentration-time curve. Renal clearance of BIA 2-005 (20 mL/min) appeared to be constant over the dose range studied, indicating that the dose-dependent urinary recovery was due either to increased formation of BIA 2-005 with increasing dose level or to decreased non-renal elimination of the metabolite. Conclusion: BIA 2-093 undergoes extensive metabolism to BIA 2-005 and was well tolerated at oral doses of 20-1200mg.The results provide a basis for further clinical trials with BIA 2-093.