{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:18:26Z","timestamp":1788952706141,"version":"build-2803163510"},"reference-count":24,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HHSN275201000003I"],"award-info":[{"award-number":["HHSN275201000003I"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Children represent a highly complex and variable population for treatment, including interindividual differences in drug dose\u2013exposure. Midazolam has been used as a sedative for hospitalized children on\u2010 and off\u2010label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under\u2010 or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure. The goal of this study was to use two modeling strategies to evaluate dose\u2013exposure of midazolam in children with and without obesity. Population pharmacokinetic modeling assessed whether measures of obesity status would explain some of the observed IIV for midazolam clearance. In all, 164 plasma concentrations were collected from 93 participating children, many with obesity. Covariate modeling did not identify any factors influential to clearance beyond body weight. Model IIV was similar to that observed in previous models of critically ill children (coefficient of variation, 175%) along with considerable residual unexplained variability (50.4%). Then, a previously published virtual population of children with obesity was incorporated into an existing physiologically based pharmacokinetic model of midazolam in the open\u2010source PK\u2010Sim software. Dosing simulations for a subset of 46 participants demonstrated minor overpredictions in children with obesity compared to those without. Both models predicted a minor (&lt;\u200920%) increase in exposure for children with obesity given the same weight\u2010based dose. This research demonstrates the use of population pharmacokinetics combined with physiologically based pharmacokinetic modeling to compare simulated exposures in children with and without obesity.<\/jats:p>","DOI":"10.1111\/cts.70247","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:28:51Z","timestamp":1747186131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real\u2010World Data"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-5398","authenticated-orcid":false,"given":"Sean","family":"McCann","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy  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  Chapel Hill North Carolina USA"}],"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":"Duke Clinical Research Institute  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7690-0695","authenticated-orcid":false,"given":"William J.","family":"Muller","sequence":"additional","affiliation":[{"name":"Ann &amp; Robert H. Lurie Children's Hospital of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0571-7492","authenticated-orcid":false,"given":"John N.","family":"van den Anker","sequence":"additional","affiliation":[{"name":"Children's National Hospital  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6532-7117","authenticated-orcid":false,"given":"Amira","family":"Al\u2010Uzri","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8400-5187","authenticated-orcid":false,"given":"Marisa L.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Division of Critical Care, Department of Pediatrics Nemours Children's Hospital  Wilmington Delaware USA"},{"name":"Department of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-0446","authenticated-orcid":false,"given":"Sarah G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"The Emmes Company, LLC  Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitora","family":"Turdalieva","sequence":"additional","affiliation":[{"name":"The Emmes Company, LLC  Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9014-1653","authenticated-orcid":false,"given":"Andrea N.","family":"Edginton","sequence":"additional","affiliation":[{"name":"University of Waterloo  Waterloo Ontario Canada"}],"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 Pediatric Trials Network Steering Committee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20103\u2010540\u201074806\u20109_16"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0736\u20104679(97)00022\u2010x"},{"key":"e_1_2_12_4_1","unstructured":"Midazolam Package Insert (US).Fresenius Kabi2017."},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00679782"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild\u20102013\u2010305720"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201510\u20102114OC"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.1004"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010014\u20100166\u2010x"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010019\u201000838\u20101"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12693"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15020440"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228\u2010014\u20101740\u20108"},{"key":"e_1_2_12_14_1","unstructured":"Open Systems Pharmacology \u201cPBPK Model Library: Midazolam.\u201d(2023) accessed June 28 2024 https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/OSP\u2010PBPK\u2010Model\u2010Library\/tree\/master\/Midazolam."},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.000318"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aer057"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12924"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010021\u201001072\u20104"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287394.2019.1652215"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15112565"},{"issue":"4","key":"e_1_2_12_21_1","first-page":"237","article-title":"Midazolam: A Review of Its Use for Conscious Sedation of Children","volume":"15","author":"Kupietzky A.","year":"1993","journal-title":"Pediatric Dentistry"},{"key":"e_1_2_12_22_1","series-title":"Vital Health Statistics Series 11 Data From the National Health Survey","first-page":"1","volume-title":"2000 CDC Growth Charts for the United States: Methods and Development","author":"Kuczmarski R. 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