Physiologically Based Pharmacokinetic Modeling of Clobazam and Stiripentol Co-Therapy in Dravet Syndrome
Abstract
Background: Dravet syndrome, a severe early-onset epileptic encephalopathy, is treated with multiple antiepileptic drugs such as clobazam (CLB) and stiripentol (STP), increasing the risk of drug–drug interactions (DDIs). Given the limited pediatric pharmacokinetic data, this study developed physiologically based pharmacokinetic (PBPK) models for CLB and STP to optimize dosing and assess DDI risk across pediatric age groups. Methods: We developed PBPK models for CLB, its active metabolite, N-desmethylclobazam (N-CLB), and STP in healthy adults and pediatric patients with Dravet syndrome aged two years and older. We evaluated the inhibitory effect of STP on CLB and N-CLB metabolism, accounting for CYP2C19 phenotypes. The model was extrapolated to predict drug exposure in pediatric patients under two years of age. Results: PBPK models for CLB, N-CLB, and STP successfully recapitulated observed pharmacokinetics in healthy adults and pediatric patients older than two years. Model verification against clinical DDI data showed that co-administration of STP with CLB resulted in a clinically insignificant increase in CLB exposure (Cmin ratio = 1.77). In contrast, N-CLB exposure increased approximately 7-fold in CYP2C19 extensive metabolizers (Cmin ratio ≈ 7) and slightly decreased in poor metabolizers (Cmin ratio = 0.9), consistent with the CYP2C19-dependent metabolism of N-CLB. Extrapolation to pediatric patients under two years of age predicted CLB, N-CLB, and STP exposures that…
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