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Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and\/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.<\/jats:p>","DOI":"10.1002\/jcph.1538","type":"journal-article","created":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T03:09:32Z","timestamp":1575947372000},"page":"453-465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients"],"prefix":"10.1002","volume":"60","author":[{"given":"Brooks T.","family":"McPhail","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Biomedical Sciences University of South 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