Abstracts

Rationale: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand which also displays inhibitory activity at neuronal voltage-dependent sodium channels and is currently in Phase III development for epilepsy. Antiepileptic drugs are usually administrated orally, but alternative routes of drug delivery may be required when oral administration is not feasible, e.g., due to swallowing problems or when used perioperatively, to avoid destabilizing seizure control. The purpose of this study was to initiate clinical development of BRV via the intravenous (IV) route. Methods: In part A of the study, using a randomized, open-label, 3-way cross-over design, the bioavailability of 10 mg BRV (10 mg/mL) single dose given as 15-minute IV infusion and as a fast IV bolus was compared to that of a 10-mg oral tablet in 24 healthy subjects (12 males, 12 females). In part B of the study, a single-dose escalation (25 mg, 50 mg, 100 mg and 150 mg) was performed in 4 consecutive groups of 6 healthy subjects (3 males, 3 females) to gain information on safety and tolerability of BRV administered as 15 minute intravenous (IV) infusion and as IV bolus (50 mg/min), as well as to assess the pharmacokinetics of BRV at these doses and to explore dose proportionality. Results: Part A: BRV 10 mg administered via 15-minute IV infusion and via IV bolus was bioequivalent to a single dose of BRV 10 mg oral tablet (90% confidence intervals of geometric ratios of both C_max and AUC within the bioequivalence range of 80-125%) (Table 1). All reported treatment-emergent adverse events (TEAEs) were mild to moderate. The most frequent TEAEs were headache (20.8%), fatigue (16.7%) and somnolence (12.5%). Their incidence was similar across the 3 BRV treatment periods. All TEAEs resolved before the end of the study. Part B: All reported TEAEs were mild to moderate. The most frequent TEAEs were somnolence (87.5%), fatigue (54.2%), dizziness (41.6%), feeling drunk (25.0%) and dysgeusia (25.0%). All these TEAEs resolved before the end of the study. None of the TEAEs led to an early study discontinuation. No SAEs and no other significant TEAEs occurred. Pharmacokinetic parameters of BRV [25 mg-150 mg] after IV infusion and IV bolus were similar. Extent of exposure (AUC) was proportional to the administered dose and dose independence was confirmed (Table 2). Conclusions: In healthy subjects, BRV 10 mg given IV as 15-min infusion or as IV bolus was bioequivalent to the 10 mg oral tablet. Pharmacokinetics were dose-proportional after IV administration. BRV [10 mg-150 mg] administered as IV infusion or IV bolus was well tolerated in healthy subjects. The clinical and pharmacokinetic results of this study support further clinical development of BRV via the IV route. Study sponsored by UCB.