Pregabalin Population Pharmacokinetic and Exposure-Response Analyses for Focal Onset Seizures in Children (4-16 years) and Adults, to Support Dose Recommendations in Children.

Abstract

Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure–response (E‐R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E‐R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one‐compartment disposition model was used, with first‐order absorption and body surface area‐normalized creatinine clearance on clearance. Individual pregabalin average steady‐state concentrations were predicted and used in an E‐R analysis of efficacy. The E‐R relationship of pregabalin was similar in pediatric (4–16 years) and adult patients with FOS after accounting for differences in baseline natural log‐transformed 28‐day seizure rate and placebo effect. Population PK simulations showed that children aged 4–16 years and weighing ≥ 30 kg required pregabalin 2.5–10 mg/kg/day to achieve similar pregabalin exposure at steady‐state to adult patients receiving the approved doses of 150–600 mg/day. For children 4–16 years weighing < 30 kg, a higher pregabalin dose of 3.5–14 mg/kg/day was required to achieve equivalent exposure at steady‐state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4–16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.