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Safety, Tolerability, and Pharmacokinetic Profile of BIA 2-093, a Novel Putative Antiepileptic, in a Rising Multiple-Dose Study in Young Healthy Humans

From the Department of Research and Development, BIAL, S Mamede do Coronado, Portugal.

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (±)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t_max) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R_O, calculated from AUC_0- (day 8)/AUC_0- (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.

Key Words: BIA 2-093 • pharmacokinetics • anticonvulsants • epilepsy

Address for reprints: P. Soares-da-Silva, Department of Research & Development, BIAL, À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal.

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This article has been cited by other articles:

				L. Almeida, A. Falcao, J. Maia, D. Mazur, M. Gellert, and P. Soares-da-Silva Single-Dose and Steady-State Pharmacokinetics of Eslicarbazepine Acetate (BIA 2-093) in Healthy Elderly and Young Subjects J. Clin. Pharmacol., September 1, 2005; 45(9): 1062 - 1066. [Full Text] [PDF]