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Its absorption and disposition are primarily transporter\u2010mediated, involving intestinal absorption by OATP2B1 and efflux by BCRP; hepatic uptake by OATP1B1, OATP1B3, OATP2B1, and NTCP; and biliary excretion by BCRP and MRP2. Given its minimal metabolism, RSV serves as a model substrate for transporter\u2010based drug absorption, disposition, and DDI studies. We developed and verified a PBPK model of RSV using a middle\u2010out approach, incorporating extensive in\u00a0vitro and in\u00a0vivo data. The model was verified with &gt;\u200975 datasets, including plasma and hepatic RSV concentrations from PET imaging studies. The model successfully captured RSV PK profiles in the Caucasian, Chinese, Malay, Japanese, and Korean populations. It also accurately captured the interconversion of RSV and RSV\u2010lactone, changes in RSV PK due to OATP1B1 and BCRP polymorphisms, and DDI with rifampin or cyclosporine. Sensitivity analyses revealed that reduced hepatic OATP1B1 activity and\/or intestinal BCRP efflux are likely determinants of altered RSV PK in the third trimester. Compared to previous models, our model extensively incorporates genetic polymorphisms, ethnic variability, reversible metabolism to the lactone, DDI, and pregnancy, allowing its use in the future to facilitate RSV dose optimization in multiple populations, including pregnant individuals.<\/jats:p>","DOI":"10.1002\/psp4.70097","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T04:40:33Z","timestamp":1756183233000},"page":"2052-2064","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rosuvastatin PBPK Modeling: Incorporating Liver Concentrations and Effects of Ethnicity, Genetic Polymorphisms, Lactone Formation, DDI and Pregnancy"],"prefix":"10.1002","volume":"14","author":[{"given":"Ankit","family":"Balhara","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle WA 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