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As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH\u2010sensitive solubility, dasatinib is susceptible to enzyme\u2010mediated drug\u2013drug interactions (DDIs) with CYP3A4 perpetrators and pH\u2010dependent DDIs with acid\u2010reducing agents. This work aimed to develop a whole\u2010body physiologically\u2010based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme\u2010mediated and pH\u2010dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration\u2013time curve from the first to the last timepoint of measurement (AUC<jats:sub>last<\/jats:sub>) and maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8\/8) predicted AUC<jats:sub>last<\/jats:sub> and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%\u201380% for strong and 0%\u201370% for moderate CYP3A4 inhibitors and a 2.3\u20133.1\u2010fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient\u2010related factors, such as elevated gastric pH.<\/jats:p>","DOI":"10.1002\/psp4.13146","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T03:54:06Z","timestamp":1714622046000},"page":"1144-1159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A physiologically\u2010based pharmacokinetic precision dosing approach to manage dasatinib drug\u2013drug interactions"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0155-9861","authenticated-orcid":false,"given":"Christina","family":"Kovar","sequence":"first","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"},{"name":"Dr. Margarete Fischer\u2010Bosch Institute of Clinical Pharmacology  Stuttgart Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena Leonie Hanae","family":"Loer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 Institute of Clinical Pharmacology  Stuttgart Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura Maria","family":"Fuhr","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima Zahra","family":"Marok","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-0816","authenticated-orcid":false,"given":"Dominik","family":"Selzer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-075X","authenticated-orcid":false,"given":"Matthias","family":"Schwab","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer\u2010Bosch Institute 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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Amercian Cancer Society.Cancer facts and figures. 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