Precision dosing of perampanel in pediatric patients receiving oxcarbazepine combination therapy: physiologically based pharmacokinetic modeling and simulation

The combination of oxcarbazepine (OXC) with perampanel (PER) considerably reduces the blood concentration of PER in children, decreasing the antiepileptic effect of PER. This study aimed to predict PER exposure and provide recommendations for dose adjustment in pediatric patients. Physiologically based pharmacokinetic (PBPK) models of PER and OXC for adults and pediatrics were developed and verified, followed by drug – drug interaction (DDI) modeling and validation of the models against available pharmacokinetic data. The simulated results of the PBPK models exhibited a fold-error value between 0.5 and 2, indicating good predictive abilities; the DDI model results supported the observational results. Based on the prediction results, the recommended dosages of PER for 4–10- and 10–14-year-old children are 2–6 and 4–8 mg q.n., respectively. Additionally, the recommended doses of PER in PER with OXC combination therapy for children aged 4–10 and 10–14 years are 6–12 and 10–12 mg q.n., respectively. The PBPK and DDI models of PER were successfully established, which serve as references for the rational use of this medication in children.