Physiologically Based Pharmacokinetic Modeling-Based Evaluation of Current Carbamazepine and Valproic Acid Dosing Guidelines for Pediatric Epilepsy Treatment.

Background: Carbamazepine and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics, and maturation of drug metabolizing enzymes further complicates personalized dosing. Physiologically based pharmacokinetic (PBPK) modeling includes these mechanisms so is a promising tool to optimize dosing. Our aim was to better support pediatric drug dosing of carbamazepine and VPA.

Methods: All carbamazepine and VPA dosing simulations were conducted with Simcyp, using available carbamazepine and VPA compound models linked with adult and pediatric population models. To verify model adequacy, adult and pediatric pharmacokinetic data were retrieved from the literature to compare predicted carbamazepine and VPA concentrations with observed data. Current Dutch national dosing strategies were then simulated to evaluate their appropriateness to achieve therapeutic levels. Where doses could be optimized, alternative dosing strategies were proposed based on simulations. In addition, the effect of altered albumin levels in children on VPA was explored through simulations under conditions of +20%, average, - 20%, and - 35% age normalized reference albumin levels.

Results: Therapeutic levels of carbamazepine and VPA will be reached after 1 or 2 weeks of treatment with the current dosing strategies. Simulations suggest a carbamazepine starting dose of 10 mg/kg/day for neonates rather than 7 mg/kg/day. In addition, children aged 12-18 years may receive a higher starting dose (e.g., 400 mg/day instead of 200 mg/day) to reach therapeutic levels more quickly. For VPA, mean total VPA concentrations dropped below the therapeutic target with reduced albumin levels (i.e., - 20% and - 35%), whereas unbound levels remained within the therapeutic window.

Conclusion: Our PBPK simulations support the current pediatric drug dosing recommendations of carbamazepine and VPA. In patients with hypoalbuminemia and when higher VPA doses are needed (i.e., ≥ 30 mg/kg/day), routine determination of unbound VPA concentrations is advised to monitor free VPA concentrations. We demonstrate that PBPK modeling is a valuable tool to confirm and further optimize dosing recommendations in children. PBPK modeling provides valuable comprehensive evidence for guiding clinical practice and potentially informing pediatric drug labeling.