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Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the <jats:italic>CYP3A5<\/jats:italic> gene. Furthermore, tacrolimus is highly susceptible to drug\u2013drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole\u2010body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food\u2013drug interactions [FDIs]) and (ii) drug\u2013drug(\u2212gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK\u2010Sim\u00ae Version 10 using a total of 37 whole blood concentration\u2013time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate\u2010release and extended\u2010release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different <jats:italic>CYP3A5<\/jats:italic> genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6\/6 predicted FDI area under the curve determined between first and last concentration measurements (AUC<jats:sub>last<\/jats:sub>) and 6\/6 predicted FDI maximum whole blood concentration (C<jats:sub>max<\/jats:sub>) ratios within twofold of the respective observed ratios. In addition, 7\/7 predicted DD(G)I AUC<jats:sub>last<\/jats:sub> and 6\/7 predicted DD(G)I C<jats:sub>max<\/jats:sub> ratios were within twofold of their observed values. Potential applications of the final model include model\u2010informed drug discovery and development or the support of model\u2010informed precision dosing.<\/jats:p>","DOI":"10.1002\/psp4.12946","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T06:49:37Z","timestamp":1676875777000},"page":"724-738","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Physiologically based pharmacokinetic modeling of tacrolimus for <scp>food\u2013drug<\/scp> and <scp>CYP3A drug\u2013drug\u2013gene<\/scp> interaction predictions"],"prefix":"10.1002","volume":"12","author":[{"given":"Helena Leonie Hanae","family":"Loer","sequence":"first","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Feick","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken 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":"Dominik","family":"Selzer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Schwab","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology  Stuttgart Germany"},{"name":"Departments of Clinical Pharmacology, Pharmacy and Biochemistry University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage\u2010guided and Functionally Instructed Tumor Therapies\u201d University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donato","family":"Teutonico","sequence":"additional","affiliation":[{"name":"Translational Medicine &amp; Early Development Sanofi\u2010Aventis Research &amp; Development  Chilly\u2010Mazarin France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Frechen","sequence":"additional","affiliation":[{"name":"Bayer AG, Pharmaceuticals, Research &amp; Development Systems Pharmacology &amp; Medicine  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike","family":"van der Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy &amp; Toxicology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk Jan A. 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