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The current study developed a PBPK model of adefovir (OAT1 clinical probe) by incorporating experimental measurements of adefovir passive diffusion and OAT1\u2010mediated transport in a mechanistic kidney model for in\u00a0vitro<jats:italic>\u2013<\/jats:italic>in vivo extrapolation of its secretion and renal clearance. The adefovir model was verified with clinical data from nine studies (188 subjects) investigating a range of adefovir intravenous and adefovir\u2010dipivoxil oral doses in White, Japanese, and Chinese populations with healthy renal function. A previously verified probenecid model, incorporating in\u00a0vivo OAT1\/3 inhibitory constant estimated using OAT1\/3 endogenous biomarker (4\u2010pyridoxic acid) clinical data, was utilized. The ratio of adefovir maximal plasma concentrations (C<jats:sub>max<\/jats:sub>R) and area under the curve (AUCR) after mid\u2010to\u2010high single oral doses of probenecid was predicted within the stringent Guest criterion. With the lowest probenecid dose (0.5\u2009g), adefovir AUCR and C<jats:sub>max<\/jats:sub>R were slightly overpredicted but still within a 1.5\u2010fold error. Application of the adefovir model to patients with severe chronic kidney disease (CKD) accounted for our previously recommended additional 50% decrease in OAT1 activity beyond the decline of glomerular filtration rate. The model successfully predicted 3\u2010fold higher adefovir C<jats:sub>max<\/jats:sub> and 6\u2010fold higher AUC in patients with severe CKD relative to healthy individuals. This study reinforces the role of PBPK modeling to predict transporter\u2010mediated DDI (coupled with biomarker\u2010informed approach to optimize in\u00a0vivo inhibitory constant) and the effect of renal impairment on OAT1\/3 drugs in lieu of clinical studies.<\/jats:p>","DOI":"10.1002\/psp4.70010","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T16:13:59Z","timestamp":1741709639000},"page":"964-974","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Evaluation of Adefovir <scp>PBPK<\/scp> Model to Assess Biomarker\u2010Informed <scp>OAT1<\/scp> Drug\u2013Drug Interaction and Effect of Chronic Kidney Disease"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-9886","authenticated-orcid":false,"given":"Shawn Pei Feng","family":"Tan","sequence":"first","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, School of Health 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