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Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically\u2010based PK (PBPK) models are an attractive alternative that can account for physiologic\u2010, genetic\u2010, and drug\u2010specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label\u2010suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in <jats:italic>CYP2C19<\/jats:italic>. The adult PBPK model was scaled to children without obesity using age\u2010associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1\u2009mg\/kg total body weight, 1.2\u2009mg\/kg lean body weight, and US Food and Drug Administration\u2010recommended weight\u2010tiered dosing. Simulated concentration\u2013time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight\u2010tiered dosing resulted in the most (&gt;90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited.<\/jats:p>","DOI":"10.1002\/psp4.13167","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:53:46Z","timestamp":1717548826000},"page":"1394-1408","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Physiologically\u2010based pharmacokinetic modeling of pantoprazole to evaluate the role of <scp>CYP2C19<\/scp> genetic variation and obesity in the pediatric population"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-1789","authenticated-orcid":false,"given":"Elizabeth J.","family":"Thompson","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Department of Pediatrics Duke University Medical Center  Durham North Carolina USA"},{"name":"Duke Clinical Research Institute  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8033-1170","authenticated-orcid":false,"given":"Angela","family":"Jeong","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC 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\/0000-0002-6681-9356","authenticated-orcid":false,"given":"Vict\u00f3ria E.","family":"Helfer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC 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\/0000-0003-3744-648X","authenticated-orcid":false,"given":"Valentina","family":"Shakhnovich","sequence":"additional","affiliation":[{"name":"University of Missouri\u2010Kansas City School of Medicine  Kansas City Missouri USA"},{"name":"Divisions of Gastroenterology, Hepatology and Nutrition &amp; Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City  Kansas City Missouri USA"},{"name":"Ironwood Pharmaceuticals  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9014-1653","authenticated-orcid":false,"given":"Andrea","family":"Edginton","sequence":"additional","affiliation":[{"name":"School of Pharmacy University of Waterloo  Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4016-1680","authenticated-orcid":false,"given":"Stephen J.","family":"Balevic","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Duke University Medical Center  Durham North Carolina USA"},{"name":"Duke Clinical Research Institute  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4266-3924","authenticated-orcid":false,"given":"Laura P.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Arkansas for Medical Sciences, Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3323-1900","authenticated-orcid":false,"given":"David N.","family":"Collier","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Center for Health Disparities, Division of General Pediatrics East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8628-2130","authenticated-orcid":false,"given":"Ravinder","family":"Anand","sequence":"additional","affiliation":[{"name":"The Emmes Company, LLC  Rockville Maryland 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":"Duke Clinical Research Institute  Durham North Carolina USA"},{"name":"Division of Clinical Pharmacology, Department of Medicine Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Best Pharmaceuticals for Children Act \u2013 Pediatric Trials Network Steering Committee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2015.132"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2011-301195"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-007373"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/17477166.2010.491118"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00128072-200305010-00003"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e3181705ce9"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12350"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13232"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.030601"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03328.x"},{"key":"e_1_2_12_12_1","unstructured":"US Food and Drug Administration.Pantoprazole [package label]. 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