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Here, we report the development of a physiologically\u2010based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)\u2010mediated drug\u2010drug interactions (DDIs) using the open\u2010source PBPK platform PK\u2010Sim, which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physicochemical, in vitro, and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration\u2010time curve [AUCR] of 3.46 and geometric mean peak plasma concentration ratios [C<jats:sub>max<\/jats:sub>Rs] of 2.00 vs. observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and C<jats:sub>max<\/jats:sub>R of 1.86 vs. observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a C<jats:sub>max<\/jats:sub>R of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.<\/jats:p>","DOI":"10.1002\/psp4.12746","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T04:54:41Z","timestamp":1637038481000},"page":"199-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Physiologically\u2010based pharmacokinetic modeling to predict CYP3A4\u2010mediated drug\u2010drug interactions of finerenone"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1153-7167","authenticated-orcid":false,"given":"Thomas","family":"Wendl","sequence":"first","affiliation":[{"name":"Pharmaceuticals R&amp;D, Pharmacometrics Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-9392","authenticated-orcid":false,"given":"Sebastian","family":"Frechen","sequence":"additional","affiliation":[{"name":"Pharmaceuticals R&amp;D, Pharmacometrics Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3807-9036","authenticated-orcid":false,"given":"Michael","family":"Gerisch","sequence":"additional","affiliation":[{"name":"Pharmaceuticals R&amp;D, Drug Metabolism and Pharmacokinetics Bayer AG  Wuppertal Germany"},{"name":"Pharmaceuticals R&amp;D, Clinical Pharmacology Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4645-5428","authenticated-orcid":false,"given":"Roland","family":"Heinig","sequence":"additional","affiliation":[{"name":"Pharmaceuticals R&amp;D, Clinical Pharmacology Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-3423","authenticated-orcid":false,"given":"Thomas","family":"Eissing","sequence":"additional","affiliation":[{"name":"Pharmaceuticals R&amp;D, Pharmacometrics Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2025845"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.083337"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-018-0483-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-019-00547-x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-020-00610-y"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12170"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.263"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00820-x"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.10081"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.16014"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12636"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12397"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12343"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00777-x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12134"},{"key":"e_1_2_9_17_1","unstructured":"OSP.Opens Systems Pharmacology| Matlab\u2010Toolbox v8.0.10. 2021 [cited June 29 2021]. 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