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This study aimed to investigate the PK of total and unbound concentrations of imatinib and the metabolite N\u2010desmethyl imatinib in hospitalized patients with different severities of COVID\u201019, and to assess the impact of critical illness and the potential drug\u2013drug interaction with IL\u20106R inhibitors on imatinib exposure. Imatinib, N\u2010desmethyl imatinib, and AAG were quantified from collected plasma samples. The PK data was further combined with previous data from COVID\u201019 patients and chronic myelogenous leukemia\/gastrointestinal stromal tumor (CML\/GIST) patients who received imatinib. A population PK analysis was conducted using a standard sequential approach. Unbound fraction in COVID\u201019 patients admitted to the intensive care unit (ICU) and treated with IL\u20106R inhibitors was significantly elevated compared to CML\/GIST patients (4.66% vs. 3.54% [1.08%\u20138.51%]; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), despite twofold increased AAG levels. Our findings on total and unbound concentration show that cotreatment with IL\u20106R inhibitor can lead to changes in metabolism and protein binding, suggesting similar implications for other highly protein bound drugs. Consequently, total concentrations may not accurately reflect unbound target site concentrations.<\/jats:p>","DOI":"10.1002\/psp4.13299","type":"journal-article","created":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T16:54:41Z","timestamp":1740243281000},"page":"583-595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disease\u2013Drug\u2013Drug Interaction of Imatinib in <scp>COVID<\/scp>\u201019 <scp>ARDS<\/scp>: A Pooled Population Pharmacokinetic Analysis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7954-6580","authenticated-orcid":false,"given":"Medhat M.","family":"Said","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-691X","authenticated-orcid":false,"given":"Job R.","family":"Schippers","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine Amsterdam UMC, Location VUmc  Amsterdam The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-1867","authenticated-orcid":false,"given":"Leila","family":"Atmowihardjo","sequence":"additional","affiliation":[{"name":"Amsterdam Institute for Infection and Immunity  Amsterdam The Netherlands"},{"name":"Department of Intensive Care Amsterdam UMC, Location AMC  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1027-6467","authenticated-orcid":false,"given":"Yingxue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6324-4044","authenticated-orcid":false,"given":"Mick S.","family":"van der Plas","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5371-0346","authenticated-orcid":false,"given":"Harm J.","family":"Bogaard","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine Amsterdam UMC, Location VUmc  Amsterdam The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-4549","authenticated-orcid":false,"given":"Lieuwe D. 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