Abstracts

Rationale: Brivaracetam (BRV) is in Phase III development for epilepsy. According to the European guideline on medicinal products for the treatment of epileptic disorders (chmp/ewp/566/98 Rev.2), the potential pharmacodynamic (PD) interactions between alcohol and central nervous system (CNS) active products should be investigated. The primary objective of the study was to evaluate if BRV influences the psychomotor and cognitive impairing effects of ethanol. The potential pharmacokinetic (PK) interactions between BRV and ethanol were evaluated as secondary objectives. Methods: This was a single-center, double-blind, randomized, placebo-controlled, 3-way crossover study in 18 healthy male subjects who received the following treatments, separated by wash‑out periods of at least 1 week: ● Treatment A: Ethanol iv infusion + BRV tablets ● Treatment B: Placebo iv infusion + BRV tablets ● Treatment C: Ethanol iv infusion + placebo tablets Ethanol or matching placebo (5% glucose solution) was administered as a 5.5 hour iv clamp (0.5 hours loading phase, followed by 5 hours at a steady-state level of 0.6 g/L). Brivaracetam or matching placebo was administered as a single oral dose of 200 mg, ensuring at least the same exposure as steady-state BRV 100 mg twice daily dosing. The following PD variables were assessed: saccadic eye movements; smooth pursuit eye movements; adaptive tracking; body sway; Bond and Lader visual analogue scales (VAS); alcohol effect VAS; Visual Verbal Learning Test (VVLT: immediate recall, immediate recognition, delayed recall, and delayed recognition). Breath ethanol, serum ethanol, and BRV plasma concentration were determined over time. PD variables and PK parameters were analyzed by mixed model analysis of variance. Results: Co-administration of BRV and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and VAS alertness; and a larger increase from baseline in body sway and in saccadic reaction time compared with BRV alone or ethanol alone. The combined treatment also increased the VAS score for alcohol effect. The immediate word recall scores were generally lower for BRV when co‑administered with ethanol, while the delayed word recall test did not show clear additional effects. A post-hoc exploratory analysis compared the PD test results for (BRV+Ethanol) with the values expected in case of additive effects ([BRV]+[Ethanol]-[Predose]). The analysis concluded that all observed effects for the BRV+Ethanol combination were additive except for the impairment of adaptive tracking which appeared to be slightly supra-additive. The maximum plasma concentration of BRV was lower when BRV and ethanol were combined (mean ratio 0.884; 90%CI 0.786-0.995), while the AUC(0-t) and AUC(0-inf) remained unchanged. In addition, BRV did not alter the total dose of ethanol required to maintain the 0.6 g/L concentration. Conclusions: Administration of BRV together with ethanol was associated with additive effects on most of the measured PD variables. There was no relevant PK interaction between BRV and ethanol. UCB supported