Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam.

ABSTRACT

BACKGROUND: An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4-16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV). OBJECTIVE: To scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children. MATERIAL AND METHODS: An existing adult population PK/PD model for BRV was scaled to children aged from 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, an ASM binding to the same target protein as BRV. An existing adult-pediatric PK/PD model for LEV was extended using data from UCB study N01009 (NCT00175890) to include children as young as 1 month of age. The BRV population PK model was updated with data up to 180 days after first administration from BRV pediatric studies N01263 (NCT00422422) and N01266 (NCT01364597). PK and PD simulations for BRV were performed for a range of mg/kg doses to predict BRV effect in pediatric participants, and to provide dosing recommendations. RESULTS: The extended adult-pediatric LEV PK/PD model was able to describe the adult and pediatric data using the same PD model parameters in adults and children and supported the extension of the adult BRV PK/PD model to pediatric patients aged 1 month to < 4 years. Simulations predicted exposures similar to adults receiving BRV 100 mg twice daily (b.i.d.), when using 3 mg/kg b.i.d. for weight < 10 kg, 2.5 mg/kg b.i.d. for weight ≥ 10 kg and < 20 kg, and 2 mg/kg b.i.d. for weight ≥ 20 kg in children aged 1 month to < 4 years. PK/PD simulations show that maximum BRV response is expected to occur with 2-3 mg/kg b.i.d. dosing of BRV in children aged 1 month to < 4 years, with an effective dose of 1 mg/kg b.i.d. for some participants. CONCLUSION: Development of an adult-pediatric BRV PK/PD model allowed characterization of the exposure-response relationship of BRV in children aged 1 to < 4 years, providing a maximal dose allowance based on weight.