Pietro Fagiolino

Valproic acid (VPA), a widely prescribed short‐chain fatty acid for managing epilepsy, psychiatric conditions, and migraines, offers significant therapeutic benefits despite its concerning toxicity profile. This study extends our previously developed Quantitative Systems Pharmacology (QSP) model by incorporating age, sex, and formulation‐related covariates to characterize VPA‐induced toxicity across diverse populations. We developed virtual populations representing four demographic groups: toddlers (0–2 years), children (2–14 years), women (14–40 years), and men (14–40 years). Age‐appropriate dosing regimens were simulated: 35 mg/kg/day for toddlers, 25 mg/kg/day for children, and 15 mg/kg/day for adults. The model successfully predicted overall incidences of hyperammonemia (29%), hyperlipidemia (54%), and hepatotoxicity (2%), aligning with previously reported clinical data. Notably, our model revealed distinct age‐dependent toxicity patterns, with significantly lower incidences in toddlers compared to similar profiles observed in children and adult women. Formulation comparison demonstrated that extended‐release formulations showed consistent directional trends toward lower adverse effect incidences compared to delayed‐release formulations across all endpoints. The model also quantitatively assessed L‐carnitine supplementation (CS) benefits, suggesting that administering L‐carnitine at twice the VPA dose (in mg) effectively prevents hyperammonemia and maintains physiological fatty acid levels. This work advances our understanding of VPA‐induced toxicity mechanisms across populations and provides evidence‐based recommendations for optimizing formulation selection and CS in both pediatric and adult patients receiving VPA therapy.