Extrapolation of a Brivaracetam Exposure–Response Model from Adults to Children with Focal Seizures

INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration–effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult–pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate ‘placebo-like’ and ‘responder’ subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies. RESULTS: The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model. CONCLUSION: Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose–response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged ≥4 years. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-017-0597-2) contains supplementary material, which is available to authorized users.