Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age

P>Purpose: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to < 10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging. Methods: Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C-min) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. Key Findings: A two-compartmental population PK model with first-order absorption described the time course of topiramate C-min as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C-min and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day. Significance: This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.