Abstracts

Rationale: Brivaracetam (ucb 34714, BRV) is a novel high-affinity synaptic vesicle protein 2A ligand, which also displays weak inhibitory activity at neuronal voltage-dependent sodium channels. It is currently in Phase III development for epilepsy. BRV is rapidly and completely absorbed, and primarily eliminated by metabolism. The main biotransformation pathways involve hydrolysis of the acetamide group, CYP-mediated hydroxylation, and a combination of these (Sargentini-Maier et al, DMD 2008;36:36 45). The objective of the study (N01209) was to assess the safety, tolerability and pharmacokinetics (PK) of BRV in healthy Japanese subjects.Methods: Eight successive panels of 10 healthy male Japanese subjects received: i) single oral doses of 2.5, 10, 25, 50 and 100 mg BRV; and ii) multiple oral doses of 2.5, 10 and 50 mg BRV twice daily for 10 days. In each group, 8 subjects received BRV and 2 received a matched placebo. Adverse events (AEs), vital signs, laboratory tests and 12-lead ECGs were obtained at regular intervals. Plasma and urine were collected serially for pharmacokinetic analysis of BRV and its three main metabolites (acid [BRV-Ac], hydroxy [BRV-OH], and hydroxyacid [BRV-OHAc]). Genotyping for two CYP2C19 mutations (/*2 and /*3) frequently found in Asian populations was performed.Results: All 80 randomized subjects received BRV or placebo and 79 completed the study. Eleven AEs were reported by 9 subjects, 4 following single dose and 5 during multiple dosing. All AEs were of mild intensity and were resolved. No new observations were made relative to the known safety and tolerability profile of BRV. The PK was linear and dose proportional after single and multiple dosing. Steady-state was reached after two days of twice daily dosing. CYP2C19 genotype was identified in 69 subjects, of whom 57 had received BRV: 15 (26%) were homozygous extensive metabolizers (*1/*1); 30 (53%) heterozygous extensive metabolizers (*1/*2 or *1/*3); and 12 (21%) subjects poor metabolizers (PM; *2/*2, *2/*3 or *3/*3). Despite a 10-fold reduction in plasma and urinary BRV-OH in PM subjects, plasma clearance of BRV (CL/F) merely decreased by 30% (see Table). Cmax was unaffected. Formation of BRV-Ac and BRV-OHAc was slightly increased.Conclusions: In Japanese healthy male subjects BRV was generally well tolerated and displayed linear and dose-proportional PK. Hydroxylation of BRV is mediated by CYP2C19 and is a minor biotransformation pathway. BRV-OHAc appears to be mainly formed from BRV-Ac. BRV dose adaptation should not be necessary for subjects bearing CYP2C19 mutations, and the potential for drug-drug clinical interactions is expected to be low. Sponsored by UCB