Abstracts

Rationale: Assessment of the population pharmacokinetics (PK), safety, and efficacy of antiepileptic drugs (AEDs) in pediatric patients (pts) to identify appropriate doses is necessary to guide clinicians when prescribing AEDs for these pts. Perampanel (PER) is a once-daily oral AED for partial-onset seizures (POS) and primary generalized tonic-clonic (PGTC) seizures. We report population PK and exposure–response analyses of adjunctive PER in pediatric pts (aged 2 to <12 years [PK] or 4 to <12 years [exposure–response]) with POS or PGTC seizures compared with healthy subjects and adolescent/adult pts (aged =12 years) with POS or PGTC seizures. Methods: PK and exposure–response analyses (relationship between average PER concentration at steady state [C_av,ss] and log-transformed percentage change from Baseline in 28-day average seizure frequency or responder probability) were performed using NONMEM^® v7.3. PK analysis included pooled data from 2 Phase II/III studies in pediatric pts with POS or PGTC seizures, 20 Phase I studies in healthy subjects, and 6 Phase II/III studies in adolescent/adult pts with POS or PGTC seizures. Covariates, including age and body weight, were tested to assess between-subject variability. PK simulations (100 per age group) were performed across 5 age groups for PER 8 mg/day, with/without concomitant enzyme-inducing AEDs (EIAEDs). Exposure–response analyses were performed for POS or PGTC seizures separately. Results: The PK dataset included 2265 subjects (pediatric pts, n=127). A 2-compartment disposition model with first-order absorption and linear elimination was used. Consistent with previous PK analyses in adolescents/adults, PER apparent clearance (CL/F) increased with coadministration of EIAEDs and was not significantly affected by other covariates, including age and body weight; CL/F and derived actual exposure parameters were similar across age groups (Fig. 1). With PER 8 mg/day set as a reference, model-derived maximum concentration and area under the curve at steady state were comparable across age groups, with/without EIAEDs, indicating bioequivalent exposures in pediatrics and adults when administered at the same dose. The exposure–response dataset included 1825 pts with POS (pediatric pts, n=75) and 155 with PGTC seizures (pediatric pts, n=6). For POS, the relationship between observed percentage change in 28-day average seizure frequency and model-predicted PER C_av,ss was comparable across age groups (Fig. 2). For PGTC seizures, preliminary data based on low pediatric pt numbers (n=6) also suggested that the relationship between 28-day average seizure frequency and PER C_av,ss was similar regardless of age. The model predicted a slightly higher probability of response for POS in pts aged <12 vs =12 years. Conclusions: PER PK and exposure–response outcomes in pediatric pts with POS or PGTC seizures were similar to those in adult/adolescent pts. These data suggest that pediatric pts aged 2 to <12 years could be up-titrated to the same PER dose as pts aged =12 years to achieve exposures shown to be efficacious. Funding: Eisai Inc.