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A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUC<jats:sub>ss<\/jats:sub>, C<jats:sub>ss,min<\/jats:sub> and C<jats:sub>ss,max<\/jats:sub> for patients with CML (<jats:italic>n<\/jats:italic>\u2009=\u200968) from a real\u2010world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade\u2009\u22653 adverse drug reactions (ADRs), using the Kruskal\u2010Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC<jats:sub>0\u201024,ss<\/jats:sub> 51.2 vs. 42.7\u2009\u03bcg\u2009h\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; C<jats:sub>ss,min<\/jats:sub> 1.1 vs. 0.9\u2009\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; C<jats:sub>ss,max<\/jats:sub> 3.4 vs. 2.8\u2009\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Patients who experienced grade\u2009\u22653 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC<jats:sub>0\u201024,ss<\/jats:sub> 56.1 vs. 45.9\u2009\u03bcg\u2009h\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; C<jats:sub>ss,min<\/jats:sub> 1.2 vs. 1.0\u2009\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; C<jats:sub>ss,max<\/jats:sub> 3.7 vs. 3.0\u2009\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, \u03b1<jats:sub>1<\/jats:sub>\u2010acid glycoprotein concentrations, liver and kidney function) and medication\u2010related factors (dose, concomitant CYP2C8 modulators) contributing to the inter\u2010individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.<\/jats:p>","DOI":"10.1002\/prp2.1082","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T08:47:20Z","timestamp":1688719640000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Application of physiologically based pharmacokinetic modeling to understand real\u2010world outcomes in patients receiving imatinib for chronic myeloid leukemia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-7910","authenticated-orcid":false,"given":"Josephine A.","family":"Adattini","sequence":"first","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health The University of Sydney  Sydney 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