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Both <jats:italic>CYP2C9<\/jats:italic> and <jats:italic>VKORC1<\/jats:italic> have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug\u2013drug interactions (DDIs). This study provides a whole\u2010body physiologically\u2010based pharmacokinetic\/PD (PBPK\/PD) model of S\u2010warfarin for predicting the effects of drug\u2013drug\u2212gene interactions on S\u2010warfarin PKs and PDs. The PBPK\/PD model of S\u2010warfarin was developed in PK\u2010Sim and MoBi. Drug\u2010dependent parameters were obtained from the literature or optimized. Of the 34 S\u2010warfarin plasma concentration\u2010time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S\u2010warfarin plasma concentration\u2010time profiles with <jats:italic>CYP2C9<\/jats:italic> genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration\u2010time curve to the last measurable timepoint (AUC<jats:sub>last<\/jats:sub>) ratio within twofold of the observed values. The anticoagulant effect of S\u2010warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose\u2010adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.<\/jats:p>","DOI":"10.1002\/psp4.13123","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T05:38:21Z","timestamp":1710481101000},"page":"853-869","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A physiologically\u2010based pharmacokinetic\/pharmacodynamic modeling approach for drug\u2013drug\u2010gene interaction evaluation of S\u2010warfarin with fluconazole"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6343-8619","authenticated-orcid":false,"given":"Kuo","family":"Geng","sequence":"first","affiliation":[{"name":"Anhui Provincial Center for Drug Clinical Evaluation Yijishan Hospital of Wannan Medical College  Wuhu Anhui China"},{"name":"Wannan Medical College  Wuhu Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2263-2709","authenticated-orcid":false,"given":"Chaozhuang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacy Administration, West China College of Pharmacy Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2005-0614","authenticated-orcid":false,"given":"Xiaohu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9386-3208","authenticated-orcid":false,"given":"Xingwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Anhui Provincial Center for Drug Clinical Evaluation Yijishan Hospital of Wannan Medical College  Wuhu Anhui 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6252-6589","authenticated-orcid":false,"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Anhui Provincial Center for Drug Clinical Evaluation Yijishan Hospital of Wannan Medical College  Wuhu Anhui China"},{"name":"Wannan Medical College  Wuhu Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8178-2256","authenticated-orcid":false,"given":"Hua","family":"Sun","sequence":"additional","affiliation":[{"name":"Anhui Provincial Center for Drug Clinical Evaluation Yijishan Hospital of Wannan Medical College  Wuhu Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-5481","authenticated-orcid":false,"given":"Haitang","family":"Xie","sequence":"additional","affiliation":[{"name":"Anhui Provincial Center for Drug Clinical Evaluation Yijishan Hospital 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