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Of note, substantial increases in plasma concentrations of \u03b1<jats:sub>1<\/jats:sub>\u2010acid\u2010glycoprotein and interleukin\u20106 have been observed among patients admitted to the hospital with advanced SARS\u2010CoV\u20102 infection. A physiologically based pharmacokinetic (PBPK) approach is a useful tool to evaluate and predict disease\u2010related changes on drug pharmacokinetics. A PBPK model of imatinib has previously been developed and verified in healthy people and patients with cancer. In this study, the PBPK model of imatinib was successfully extrapolated to patients with SARS\u2010CoV\u20102 infection by accounting for disease\u2010related changes in plasma \u03b1<jats:sub>1<\/jats:sub>\u2010acid\u2010glycoprotein concentrations and the potential drug interaction between imatinib and dexamethasone. The model demonstrated a good predictive performance in describing total and unbound imatinib concentrations in patients with SARS\u2010CoV\u20102 infection. PBPK simulations highlight that an equivalent dose of imatinib may lead to substantially higher total drug concentrations in patients with SARS\u2010CoV\u20102 infection compared to that in patients with cancer, while the unbound concentrations remain comparable between the 2 patient populations. This supports the notion that unbound trough concentration is a better exposure metric for dose adjustment of imatinib in patients with SARS\u2010CoV\u20102 infection, compared to the corresponding total drug concentration. Potential strategies for refinement and generalization of the PBPK modeling approach in the patient population with SARS\u2010CoV\u20102 are also provided in this article, which could be used to guide study design and inform dose adjustment in the future.<\/jats:p>","DOI":"10.1002\/jcph.2065","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T14:19:48Z","timestamp":1650723588000},"page":"1285-1296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS\u2010CoV\u20102 Infection: A Case Study With Imatinib"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6781-2113","authenticated-orcid":false,"given":"Jeffry","family":"Adiwidjaja","sequence":"first","affiliation":[{"name":"Sydney Pharmacy School Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-7910","authenticated-orcid":false,"given":"Josephine A.","family":"Adattini","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-9286","authenticated-orcid":false,"given":"Alan V.","family":"Boddy","sequence":"additional","affiliation":[{"name":"UniSA Cancer Research Institute and UniSA Clinical &amp; Health Sciences University of South Australia  Adelaide South Australia Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4674-0242","authenticated-orcid":false,"given":"Andrew J.","family":"McLachlan","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,5,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.12839"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-021-00452-0"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020040509"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2020.05.006"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00426-4"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31404"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12718"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04422.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.21037\/tcr.2017.09.08"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2006.02719.x"},{"issue":"1672","key":"e_1_2_11_12_1","first-page":"1","article-title":"Implementation of a physiologically based pharmacokinetic modelling approach to guide optimal dosing regimens for imatinib and potential drug interactions in paediatrics","volume":"10","author":"Adiwidjaja J","year":"2020","journal-title":"Front Pharmacol"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1592\/phco.24.16.1508.50958"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.92"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.048017"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2009.12.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15084"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00237-X"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021436"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2176"},{"key":"e_1_2_11_21_1","unstructured":"European Medicines Agency Human Medicines Division.Summary on compassionate use: Remdesivir Gilead. 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