Concomitant Antiseizure Medications' Influence on Valproic Acid and Levetiracetam Pharmacokinetics in Pediatric Patients.

BACKGROUND: Valproic acid (VPA) and levetiracetam (LEV) are among the most widely used anti-seizure medications (ASMs) in pediatric epilepsy. Although they share the common goal of seizure control, these drugs exhibit distinct pharmacokinetic characteristics, which can influence therapeutic drug monitoring (TDM), dosing strategies, and treatment response. OBJECTIVE: This study aims to compare the intra-drug pharmacokinetic profiles of VPA and LEV in pediatric patients, focusing on dose-normalized concentration (C0/mg/kg). The study also investigates the impact of concomitant enzyme-inducing or enzyme-inhibiting drugs on these parameters. METHODS: The analysis included 1141 serum samples from 817 patients (447 VPA; 370 LEV). Pediatric patients receiving monotherapy or combination therapy with one of two anti-seizure medications were retrospectively analyzed. Pharmacokinetic indices were compared using descriptive and nonparametric methods. Subgroup analysis was performed according to concomitant drugs affecting liver metabolism. RESULTS: A moderately positive correlation was observed between daily LEV dose and serum concentration (r = 0.47, p < 0.0001), while VPA showed a weaker but significant dose-concentration relationship (r = 0.31, p < 0.001; R2 = 0.096). Dose-normalized minimum concentrations (C0/mg/kg) differed significantly between treatment groups for both drugs. In the VPA group, concomitant use of enzyme inducers was associated with significantly lower C0/mg/kg values compared with both monotherapy and neutral co-medication groups (p < 0.001). Similarly, the LEV+ inducer group showed significantly different C0/mg/kg values than levetiracetam monotherapy (p = 0.005). Neutral concomitant drugs did not significantly affect C0/mg/kg for either drug. CONCLUSION: Concomitant enzyme-inducing ASM significantly reduced dose-normalized trough concentrations of VPA and LEV, while neutral co-medications had no effect, highlighting the importance of TDM in pediatric combination therapy.