Evaluation of brivaracetam efficacy as monotherapy in adult patients with focal seizures

摘要

Highlights ? This article describes population PK and PD of BRV in add-on & monotherapy settings. ? Data from 3 add-on and 2 incomplete monotherapy BRV Phase III trials were used. ? Steady-state plasma concentration estimates for monotherapy: 22.6% higher vs add-on. ? Only minor changes in the dose-response relationship are expected for monotherapy. ? Results suggested that dose modifications are not warranted for BRV monotherapy. Abstract Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. The goal of the present analysis was to determine if the dose-response of brivaracetam as monotherapy would fall within the range associated with brivaracetam efficacy as adjunctive therapy. An existing brivaracetam population pharmacokinetic model consisting of first-order absorption, single compartment distribution, and first-order elimination components was extended by estimating the clearance changes due to co-administration of 12 widely prescribed AEDs. Data for the population pharmacokinetic analysis originated from three Phase III add-on trials and two terminated Phase III monotherapy trials. An existing population model of daily seizure rate versus brivaracetam daily average concentration was applied to the data from the three add-on trials. Simulations allowed the assessment of the combined impact of covariate effects on both the pharmacokinetics and the pharmacodynamics of brivaracetam, and indicated that in the absence of other AEDs, only marginal changes in the overall dose-response relationship would be expected. This suggests that brivaracetam can be used as monotherapy without dose modifications.