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Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate\u2010glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug\u2013drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically\u2010based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in\u00a0vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration\u2010time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7\u2010fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non\u2010wild\u2010type variants for both isoforms. This study is a first cornerstone to qualify the PK\u2010Sim platform for use of UGT\u2010mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.<\/jats:p>","DOI":"10.1002\/psp4.13059","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T06:15:30Z","timestamp":1696486530000},"page":"79-92","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Applied physiologically\u2010based pharmacokinetic modeling to assess uridine diphosphate\u2010glucuronosyltransferase\u2010mediated drug\u2013drug interactions for Vericiguat"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-9392","authenticated-orcid":false,"given":"Sebastian","family":"Frechen","sequence":"first","affiliation":[{"name":"Pharmacometrics\/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Ince","sequence":"additional","affiliation":[{"name":"Pharmacometrics\/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-5719","authenticated-orcid":false,"given":"Andr\u00e9","family":"Dallmann","sequence":"additional","affiliation":[{"name":"Pharmacometrics\/Modeling and Simulation, Research and Development Pharmaceuticals, 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":"DMPK, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A.","family":"Jungmann","sequence":"additional","affiliation":[{"name":"DMPK, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina","family":"Becker","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Lobmeyer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Research and Development Pharmaceuticals, Bayer AG  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Trujillo","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  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