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Acceptance of COC drug\u2013drug interaction (DDI) assessment using physiologically\u2010based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate\/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision\u2010tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model\u2010informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.<\/jats:p>","DOI":"10.1002\/psp4.13101","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T05:48:44Z","timestamp":1703224124000},"page":"563-575","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Physiologically\u2010based pharmacokinetic modeling of prominent oral contraceptive agents and applications in <scp>drug\u2013drug<\/scp> interactions"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8758-7421","authenticated-orcid":false,"given":"Gareth 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