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Existing pharmacokinetic (PK) models often lack detailed representation of intracellular disposition and metabolism. We developed a dual minimal physiologically based pharmacokinetic (mPBPK) model incorporating mechanistic uptake and metabolism in hepatocytes and peripheral blood mononuclear cells (PBMCs) to characterize the systemic and intracellular kinetics of TAF, tenofovir (TFV), and TFVdp. The model was calibrated using diverse clinical datasets, including TFV intravenous dosing and oral TAF administration in people with and without HIV. It accurately captured plasma and PBMC profiles of all three analytes across single and multiple dosing regimens. Global sensitivity analysis identified hepatic phosphorylation, permeability, and PBMC\u2010specific processes as primary determinants of systemic TFV and intracellular TFVdp levels. Hepatic uptake and retention of TAF were inversely associated with PBMC TFVdp concentrations, suggesting competition between liver and PBMCs for TAF distribution. The model supports TFVdp in PBMCs as a robust biomarker of adherence and highlights potential strategies to enhance PBMC targeting while limiting systemic TFV exposure. This mechanistic framework provides a valuable tool for optimizing TAF\u2010based therapies, informing drug design, and evaluating alternative dosing strategies or formulations. The model is broadly applicable to other intracellularly activated antivirals and supports precision pharmacotherapy in HIV prevention and treatment.<\/jats:p>","DOI":"10.1002\/cpt.70097","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T19:50:23Z","timestamp":1762199423000},"page":"490-502","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Minimal Physiologically Based Pharmacokinetic Model of Tenofovir Alafenamide and Its Metabolites in Humans"],"prefix":"10.1002","volume":"119","author":[{"given":"Weihua","family":"Jiang","sequence":"first","affiliation":[{"name":"Division of Pharmacokinetics\u2010Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences The State University of New York at Buffalo  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3932-7185","authenticated-orcid":false,"given":"Sukyung","family":"Woo","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics\u2010Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences The State University of New York at Buffalo  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"Vemlidy (tenofovir alafenamide) [prescribing information]. 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