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The risk assessment of bosentan\u2010induced liver injury requires a thorough understanding of the underlying mechanisms, for which there is accumulating evidence. Integrating these mechanisms with clinical liver bosentan concentration would enable a more dynamic and relevant risk assessment. This study designed a workflow of physiologically\u2212based pharmacokinetic (PBPK) model development to capture bosentan's hepatic disposition and predict the (intra)hepatic bosentan exposure. Specifically, clinical plasma and excretion data of bosentan were used to minimize the uncertainty in estimating the hepatic clearance. The model predictions were well overlapped with observations in the systemic circulation and excretion. Furthermore, the model\u2010derived intrinsic hepatic clearance was comparable with the one derived from a clinical study. These results reflected confidence in the model's capability to predict hepatic bosentan exposure. The model\u2010simulated steady\u2010state unbound exposure to bosentan in hepatocytes and liver tissue ranged from 1.65 to 34.1\u2009ng\/mL following twice\u2010daily 125\u2010mg oral doses. The ratio of the simulated unbound concentration between the liver matrices and systemic plasma was between 0.80 and 2.93 across the therapeutic dosing regimens. In summary, a bosentan PBPK model was successfully developed with the designed workflow and was able to predict the hepatic disposition of bosentan. The developed model can be applied to generate hepatic bosentan exposure that bridges the toxicological mechanistic findings from in\u00a0vitro to in\u00a0vivo, assisting in risk assessment.<\/jats:p>","DOI":"10.1002\/psp4.70085","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T23:40:14Z","timestamp":1754437214000},"page":"1715-1726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Predicting Systemic and Liver Bosentan Exposure Using Physiologically\u2010Based Pharmacokinetic Modeling"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-039X","authenticated-orcid":false,"given":"Miao\u2010Chan","family":"Huang","sequence":"first","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-5867","authenticated-orcid":false,"given":"Julia","family":"Macente","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6791-5040","authenticated-orcid":false,"given":"Sofie","family":"Heylen","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5697-999X","authenticated-orcid":false,"given":"Chen","family":"Ning","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3280-2158","authenticated-orcid":false,"given":"Kristof","family":"De Vos","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5014-1691","authenticated-orcid":false,"given":"Neel","family":"Deferm","sequence":"additional","affiliation":[{"name":"Pharmides BV  Pelt Belgium"},{"name":"Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-7351","authenticated-orcid":false,"given":"Pieter","family":"Annaert","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"},{"name":"BioNotus CommV  Niel Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"\u201cU.S. Food and Drug Administration Drug Approval Package: Tracleer (Bosentan) Tablets \u201d(2001). 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