Abstracts

Rationale: To describe the individual change in seizure frequency from baseline after treatment with brivaracetam or placebo, to model the dose-response relationship and to assess the impact of potential covariates.Methods: Seizure count data were pooled from 2 double-blind, placebo-controlled, parallel-group, phase-IIB trials in 363 patients, aged 16-65 years. All patients were on stable regimens with 1 or 2 concomitant antiepileptic drugs (AEDs). Brivaracetam dose levels were 0, 5, 20, 50 and 150 mg/day. Individual seizure frequency was modeled in NONMEM as a Poisson process, expressed as a function of baseline seizures, drug treatment, placebo effect and subject-specific random effects. The Mixture function was used for partitioning the population into 2 subgroups of patients, exhibiting decreased or increased seizure frequency compared with baseline. In the first group, the drug effect was modeled using an Emax dose-response function on top of the placebo effect, whereas the change in seizure frequency in non-improving patients was dose-independent. In a second step, an exposure-response model was built by replacing the dose with individual posterior estimates of exposure (AUCτ) derived from population PK modeling.Results: The database included 106, 50, 52, 104 and 51 patients on placebo, 5, 20, 50 and 150 mg/day brivaracetam, respectively. Overall, 73% of patients were classified as having decreased seizures and 27% increased seizures on brivaracetam, compared with 57% and 43% on placebo, respectively. In patients improving on brivaracetam, the mean ED50 was predicted to be 21 mg/day and the mean maximum seizure reduction from baseline was 70%. The mean seizure reduction in patients improving on placebo was 41%. The mean seizure increase in non-improving patients (brivaracetam and placebo) was 11%. Age, bodyweight, gender, carbamazepine, phenytoin and the number of concomitant AEDs were found not to affect the percentage of patients likely to improve, or the extent of change in seizure frequency. The proportion of patients with decreased seizures on brivaracetam was higher in Indian/Pakistani/Hispanic than in Caucasian/other ethnic groups and was higher without than with concomitant levetiracetam. The exposure-response model did not result in any fitting improvement over the dose-response model and the EC50 was 2.1 mg.h/L, corresponding to 10 mg BID dosing.Conclusions: Emax-modeling of Poisson-transformed seizure count data demonstrated a dose-response relationship for brivaracetam in 73% of the patients with refractory partial-onset seizures. A dose of 20 mg daily is expected to decrease seizure frequency by 50% of the maximum possible change from baseline. UCB funded