Abstracts

Rationale: Brivaracetam is a novel, high-affinity synaptic vesicle protein 2A ligand and also displays inhibitory activity at neuronal voltage-dependent sodium channels. It is currently in Phase III development for epilepsy. It is rapidly and completely absorbed, and primarily eliminated by metabolism, with the major metabolic pathways including hydrolysis of the acetamide group, CYP-mediated hydroxylation and a combination of these (Sargentini-Maier et al., Drug Metab Dispos 2008;36:36-45). The objective of this study was to characterize the effect of increasing hepatic impairment on brivaracetam disposition relative to matched healthy controls. Methods: Twenty-six subjects (aged 37-71 years; 7 female, 19 male) stratified according to Child-Pugh classification for mild (class A; n=6), moderate (class B; n=7) and severe (class C; n=7) hepatic impairment and matched healthy controls (n=6) received a single oral dose of 100 mg brivaracetam. Plasma and urine concentrations of brivaracetam and metabolites were measured over 96 hours (h). Brivaracetam plasma protein binding was measured in samples obtained 1 h post-dose. Functional hepatic plasma flow and hepatic metabolic function were assessed by the D-sorbitol test and antipyrine test, respectively. Results: Relatively to healthy controls, functional hepatic plasma flow was 85%, 66% and 52% and hepatic metabolic function was 37%, 19% and 22% in subjects with mild, moderate and severe impairment. The mean plasma half-life of brivaracetam increased from 9.8 h in healthy controls to 14.2, 16.4 and 17.4 h in the mild, moderate and severe impairment groups. The area under the plasma concentration-time curve (AUCinf) of brivaracetam was 29.7 μg.h/mL in healthy controls and 1.5-1.6-fold higher (44.6, 46.7 and 47.1 μg.h/mL) in patients. Likewise, the AUC of the carboxylic acid metabolite was 1.6-1.9-fold higher in diseased subjects than in healthy controls. On the opposite, the AUC of the hydroxy metabolite was reduced to 62%, 35% and 21% of healthy controls. The hydroxy-acid metabolite was only reduced (50% of controls) in the severe impairment group. The protein binding of brivaracetam was 20% in subjects with normal or mildly impaired liver function, 16% in subjects with moderate impairment and 17% in subjects with severe hepatic impairment. The incidence of adverse events was similar across the four treatment groups; all adverse events were mild to moderate. Conclusions: The relative importance of brivaracetam biotransformation pathways is altered in subjects with hepatic impairment, with a decrease in the CYP-dependent hydroxylation pathways and a concomitant increase in the formation of the acid metabolite (pharmacologically inactive). In subjects with liver impairment, dose adjustment is not mandatory but the starting dose may be considered on a case-by-case basis according to individual response and safety/tolerability. Study sponsored by UCB.