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

Abstract

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.

Fig. 1

VPC for the final levetiracetam PK/PD model by dose and adults/children for median % change from baseline. Histograms provide the distribution of outcomes for 500 simulated trials, the blue vertical line displays the result for the observed data, and grey areas encompass 95% of simulated trial outcomes. The 60 mg/kg/day panel for children indicates the active treatment where the applied dose was targeted to provide a similar exposure as 3000 mg/day for adults. PK/PD pharmacokinetic/pharmacodynamic, VPC visual predictive check

Fig. 2

VPC for the final levetiracetam PK/PD model by dose and adults/children for proportion ≥ 50% responders. Histograms provide the distribution of outcomes for 500 simulated trials, the blue vertical line displays the result for the observed data, and the grey areas encompass 95% of the simulated trial outcomes. The 60 mg/kg/day panel for children indicates the active treatment where the applied dose was targeted to provide a similar exposure as 3000 mg/day for adults. PK/PD pharmacokinetic/pharmacodynamic, VPC visual predictive check

Fig. 3

Overall simulated brivaracetam effect (left) and split by mixture-model population (right), in children, by C _av (top) and daily dose with a maximum of 200 mg/day (bottom). Median (blue line) and interquartile range of simulated individuals. Dashed vertical line (top) indicates EC₅₀. C _av average steady-state concentration, EC ₅₀ concentration associated with 50% of the maximum effect

Fig. 4

Simulated brivaracetam effect by daily dose, with a maximum of 200 mg/day, and age for the mixture-model responder population. Median (blue line), and interquartile range of simulated children