Brivaracetam disposition in renal impairment

Abstract

Brivaracetam is a novel high-affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/min, n = 6; 15-29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The C(max) of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01-1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m(2). Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: C(max) by 2.4-, 2.0-, and 11.7-fold and AUC by 3.2-, 4.1-, and 21.5-fold. Renal clearance of these rapidly cleared metabolites was decreased 10-fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction.