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Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically\u2010based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity\u2010induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2\u00a0\u03bcg\/kg\/h) starting at an earlier age (6\u2009years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady\u2010state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (<jats:italic>CYP<\/jats:italic>)<jats:italic>2B6*6\/*6<\/jats:italic> virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically\u2010based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.<\/jats:p>","DOI":"10.1002\/psp4.12793","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T08:30:39Z","timestamp":1651480239000},"page":"778-791","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Use of <scp>physiologically\u2010based<\/scp> pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4679-4638","authenticated-orcid":false,"given":"Jacqueline G.","family":"Gerhart","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4921-5235","authenticated-orcid":false,"given":"Fernando O.","family":"Carre\u00f1o","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1740-5704","authenticated-orcid":false,"given":"Jennifer L.","family":"Ford","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9014-1653","authenticated-orcid":false,"given":"Andrea\u00a0N.","family":"Edginton","sequence":"additional","affiliation":[{"name":"School of Pharmacy University of Waterloo  Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8876-730X","authenticated-orcid":false,"given":"Eliana M.","family":"Perrin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine and School of Nursing Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5975-5091","authenticated-orcid":false,"given":"Kevin M.","family":"Watt","sequence":"additional","affiliation":[{"name":"Division of Pediatric Clinical Pharmacology, School of Medicine University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Muller","sequence":"additional","affiliation":[{"name":"Ann and Robert H. Lurie Children's Hospital of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4744-3832","authenticated-orcid":false,"given":"Andrew M.","family":"Atz","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina Children's Hospital  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Al\u2010Uzri","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Delmore","sequence":"additional","affiliation":[{"name":"Wesley Medical Center  Wichita Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-5686","authenticated-orcid":false,"given":"Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Best\u00a0Pharmaceuticals for Children Act\u2013Pediatric Trials Network Steering Committee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2017-3459"},{"key":"e_1_2_9_3_1","unstructured":"World Health Organization.Report of the commision on ending childhood obesity. 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