Dose-response population modeling of the new antiepileptic drug brivaracetam in add-on treatment of partial onset seizures.
Christian Laveille(1), Eric Snoeck(1), Brigitte Lacroix(2), Maria Laura Sargentini-Maier(2), Armel Stockis(2)
(1) Exprimo, Lummen, Belgium; (2)UCB Pharma, Braine-l'Alleud, Belgium.
Objectives: 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: Efficacy data were used from two double-blind, placebo-controlled parallel-group phase-IIB trials in 363 patients aged 16-65 years. Brivaracetam dose levels were 0, 5, 20, 50 and 150 mg/day. Individual seizure frequency was modeled with NONMEM (version V) 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 in two subgroups of patients exhibiting decreased or increased seizure frequency compared to 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, the dose was replaced by individual posterior estimates of AUCtau in the Emax model.
Results: 73% of the patients were classified as improving on brivaracetam, compared to 57% on placebo. In improving patients, the ED50 was predicted to be 21 mg/day and the maximum seizure reduction from baseline was 70%. The mean seizure reduction in patients improving on placebo was 41%. The mean increase in non-improving patients was 11%. Age, bodyweight, gender, carbamazepine, phenytoin, and the number of concomitant AEDs were found to neither affect the percentage of patients who are likely to improve nor the extent of change in seizure frequency, while country and concomitant levetiracetam influenced the effect size. The concentration-response model did not result in any improvement over the dose-response model.
Conclusions: Emax-modeling of Poisson-transformed seizure count data allowed to demonstrate a dose-response relationship for brivaracetam in 73% of the patients with refractory partial seizures. A dose of 20 mg daily is expected to decrease the seizure frequency by 50% of the maximum from baseline.