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This study extends our previously developed Quantitative Systems Pharmacology (QSP) model by incorporating age, sex, and formulation\u2010related covariates to characterize VPA\u2010induced toxicity across diverse populations. We developed virtual populations representing four demographic groups: toddlers (0\u20132\u2009years), children (2\u201314\u2009years), women (14\u201340\u2009years), and men (14\u201340\u2009years). Age\u2010appropriate dosing regimens were simulated: 35\u2009mg\/kg\/day for toddlers, 25\u2009mg\/kg\/day for children, and 15\u2009mg\/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\u2010dependent toxicity patterns, with significantly lower incidences in toddlers compared to similar profiles observed in children and adult women. Formulation comparison demonstrated that extended\u2010release formulations showed consistent directional trends toward lower adverse effect incidences compared to delayed\u2010release formulations across all endpoints. The model also quantitatively assessed L\u2010carnitine supplementation (CS) benefits, suggesting that administering L\u2010carnitine at twice the VPA dose (in mg) effectively prevents hyperammonemia and maintains physiological fatty acid levels. This work advances our understanding of VPA\u2010induced toxicity mechanisms across populations and provides evidence\u2010based recommendations for optimizing formulation selection and CS in both pediatric and adult patients receiving VPA therapy.<\/jats:p>","DOI":"10.1002\/psp4.70200","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T13:57:46Z","timestamp":1769695066000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A\n                    <scp>QSP<\/scp>\n                    Model of Valproic Acid Toxicity in Pediatric and Adult Populations: Implications for Formulation Selection and L\u2010Carnitine Supplementation"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8358-8039","authenticated-orcid":false,"given":"Alejandra","family":"Schiavo","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of 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