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Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored. In this study, we aimed to individualize physiologically\u2010based pharmacokinetic (PBPK) models based on liquid biopsy measurements in plasma from 25 donors with different grades of renal function who were previously administered oral midazolam as part of a microdose cocktail. Virtual twin models were constructed based on demographics, renal function, and hepatic expression of relevant pharmacokinetic pathways projected from liquid biopsy output. Simulated exposure (AUC) to midazolam was in agreement with observed data (AFE\u2009=\u20091.38, AAFE\u2009=\u20091.78). Simulated AUC variability with three dosing approaches indicated higher variability with uniform dosing (14\u2010fold) and stratified dosing (13\u2010fold) compared with individualized dosing informed by liquid biopsy (fivefold). Further, exosome screening revealed mRNA expression of 532 targets relevant to drug metabolism and disposition (169 enzymes and 361 transporters). Data related to these targets can be used to further individualize PBPK models for pathways relevant to PK of other drugs. This study provides additional verification of liquid biopsy\u2010informed PBPK modeling approaches, necessary to advance strategies that seek to achieve precise dosing from the start of treatment.<\/jats:p>","DOI":"10.1002\/cpt.3291","type":"journal-article","created":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T09:35:59Z","timestamp":1715592959000},"page":"814-823","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Dealing With Variable Drug Exposure Due\u00a0to\u00a0Variable Hepatic Metabolism: A Proof\u2010of\u2010Concept Application of Liquid Biopsy in Renal Impairment"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami\u2010Hodjegan","sequence":"first","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, School of Health Sciences University of Manchester  Manchester UK"},{"name":"Certara  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-3140","authenticated-orcid":false,"given":"Zubida M.","family":"Al\u2010Majdoub","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, School of Health Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-6953","authenticated-orcid":false,"given":"Yannick","family":"von Grabowiecki","sequence":"additional","affiliation":[{"name":"Cancer Research UK Manchester Institute University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3099-4440","authenticated-orcid":false,"given":"Ka Lai","family":"Yee","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  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