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This study established an adult physiological\u2010based pharmacokinetic\/pharmacodynamic (PBPK\/PD) model in the modeling software and extended it to neonates using pediatric extrapolation strategies based on maturation formulas for plasma albumin and CYP3A4\/5. The neonatal model was then utilized to simulate midazolam dosage regimens for sedation in newborns. Individualized validation for adults indicated that 95.1% of predicted concentration values and all area under curve (AUC) values fell within a 2\u2010fold range. The extrapolated neonatal model showed 84.4% of predicted concentrations within 2\u2010fold, an absolute average fold error (AAFE) valuen &lt;2, and an average fold error (AFE) value between 0.5 and 1.5, confirming the model's adequacy. The validated neonatal PBPK\/PD model indicated that virtual term neonates maintained the target plasma concentration for 25\u00a0hours with the recommended dosage (0.06\u00a0mg\/kg\/h, intravenous infusion 12\u00a0hours). Premature infants may require a slightly higher dose than the label's recommendation (0.03\u00a0mg\/kg\/h, intravenous infusion 12\u00a0hours). Our findings recommend this research strategy based on extrapolation and model simulation for drug dose prediction and optimization in the neonatal population.<\/jats:p>","DOI":"10.1002\/cpdd.1531","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T14:06:29Z","timestamp":1745503589000},"page":"415-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extrapolation of Midazolam Disposition in Neonates Using Physiological\u2010Based Pharmacokinetic\/Pharmacodynamic Modeling"],"prefix":"10.1002","volume":"14","author":[{"given":"Tangping","family":"Zhao","sequence":"first","affiliation":[{"name":"Phase I Clinical Trial Unit The First Affiliated Hospital with Nanjing Medical University  Nanjing China"},{"name":"Department of Clinical Pharmacology Pharmacy College Nanjing Medical University  Nanjing 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