Abstracts

Rationale: For antiepileptic drugs (AEDs) approved for adult use in seizure types/syndromes also occurring in children, pharmacokinetic (PK) models developed in adults can be applied to pediatric PK data to guide dosing in children. SPN-538 (Trokendi XR^®; Supernus Pharmaceuticals, Inc.) is a once-daily, extended-release capsule formulation of topiramate (TPM). Bioequivalence to immediate-release TPM (TPM-IR; Topamax^®, Janssen Pharmaceuticals) was demonstrated in healthy adults. A population PK model developed in healthy adults and validated in adults with epilepsy was applied to PK data from children with epilepsy to determine appropriate scaling factors for pediatric dosing. Methods: Children (7-17 yrs) with focal or primary generalized epilepsy receiving stable TPM-IR BID were switched to once-daily SPN-538 for 2 wks. PK sampling: TPM-IR, one sample; SPN-538: pre- and 2, 4, 6, 8, 10 hrs post-dose on final day. PK data analyzed using linear 2-compartment model previously validated in adults with epilepsy. Data analysis: nonlinear mixed-effects modeling (NONMEM). Absorption parameters: absorption rate constant (k_a, representing both drug release and uptake), absorption lag, and relative bioavailability. Systemic parameters: apparent clearance (CL/F), apparent volume of central compartment (V₁/F), apparent distributional clearance (CL₂/F), and apparent volume of peripheral compartment (V₂/F). Model parameters fixed to adult values. Covariates investigated: body size, age, gender, race, ethnicity, TPM daily dose, and concomitant AEDs. Approaches to scaling body size: 1) allometric; 2) weight-normalized. A pediatric scaling factor was estimated to quantify systemic parameter differences for children vs adults that could not be explained by body size. Model goodness of fit evaluated with objective function (-2 x log likelihood) and graphical error analysis. Final model was validated using visual predictive check. Results: Final NONMEM analysis dataset included PK data for 29 children. TPM dose: 50-600 mg/day (~0.8-11 mg/kg/day). Model parameters estimated in adults with epilepsy described pediatric data well. After allometric scaling of body size, estimated pediatric scaling factor was 1.28, which applied equally to both clearance and volume of distribution. Concomitant use of enzyme-inducing AEDs (EIAEDs) increased TPM CL/F by a factor of 1.75. No other covariates were incorporated into the model. Conclusions: A population PK model developed in adults was successfully adapted to children. The final model fit the data well. The model indicated that TPM exposure in children should vary inversely with weight. Absolute bioavailability of TPM is lower in children than adults. After correction for weight, TPM exposure in children may be ~28% lower. Because clearance and volume of distribution are similarly affected, TPM half-life should be similar in adults and children. Results are consistent with known TPM PK parameters. This study confirms current Trokendi XR dosing recommendations of 5-9 mg/kg/day for children ages 6 yrs and older. Study sponsor: Supernus Pharmaceuticals, Inc.