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As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug\u2013drug interactions (DDIs) when co\u2010administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite <jats:italic>N<\/jats:italic>\u2010desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co\u2010medications. This work presents the development of a parent\u2013metabolite whole\u2010body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK\u2010Sim\u00ae using a total of 60 plasma concentration\u2013time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P\u2010glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12\/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUC<jats:sub>last<\/jats:sub>) ratios and 12\/12 predicted DDI maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model\u2010informed drug development or the support of model\u2010informed precision dosing.<\/jats:p>","DOI":"10.1002\/psp4.13127","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T11:38:57Z","timestamp":1710416337000},"page":"926-940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Physiologically based pharmacokinetic modeling of imatinib and <i>N<\/i>\u2010desmethyl imatinib for drug\u2013drug interaction predictions"],"prefix":"10.1002","volume":"13","author":[{"given":"Helena Leonie Hanae","family":"Loer","sequence":"first","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Kovar","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"},{"name":"Dr. Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology  Stuttgart Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-2511","authenticated-orcid":false,"given":"Simeon","family":"R\u00fcdesheim","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"},{"name":"Dr. Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology  Stuttgart Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima Zahra","family":"Marok","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Maria","family":"Fuhr","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Selzer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-075X","authenticated-orcid":false,"given":"Matthias","family":"Schwab","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology  Stuttgart Germany"},{"name":"Departments of Clinical Pharmacology, and Pharmacy and Biochemistry University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Cluster of Excellence iFIT (EXC2180), Image\u2010Guided and Functionally Instructed Tumor Therapies University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8372-1465","authenticated-orcid":false,"given":"Thorsten","family":"Lehr","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33933"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-145-12-200612190-00008"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.238"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106552"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666170523124441"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270003262101"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.048017"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2010.506873.Metabolism"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.2533\/chimia.2019.561"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4913"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.055574"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-04-1398"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.004283"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01732.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03150.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6601152"},{"key":"e_1_2_10_18_1","unstructured":"Drug development and drug interactions: FDA table of substrates inhibitors and inducers. 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