{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T09:56:30Z","timestamp":1792835790977,"version":"4.5.0"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Research, Technology and Space","doi-asserted-by":"publisher","award":["031L0304B"],"award-info":[{"award-number":["031L0304B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["436883643"],"award-info":[{"award-number":["436883643"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["465194077"],"award-info":[{"award-number":["465194077"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MBF-funded de.NBI Cloud","award":["031A537B"],"award-info":[{"award-number":["031A537B"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A533A"],"award-info":[{"award-number":["031A533A"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A538A"],"award-info":[{"award-number":["031A538A"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A533B"],"award-info":[{"award-number":["031A533B"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A535A"],"award-info":[{"award-number":["031A535A"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A537C"],"award-info":[{"award-number":["031A537C"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A534A"],"award-info":[{"award-number":["031A534A"]}]},{"name":"MBF-funded de.NBI Cloud","award":["031A532B"],"award-info":[{"award-number":["031A532B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Dapagliflozin is an SGLT2 inhibitor prescribed for the management of type 2 diabetes mellitus. The drug lowers blood glucose levels by increasing urinary glucose excretion (UGE). Despite established efficacy, dapagliflozin demonstrates significant inter-individual variability in pharmacokinetics (PK) and pharmacodynamics (PD), with potential impact on treatment outcomes. Methods: To evaluate the sources of variability and to support patient stratification and model-informed individualized therapy, we developed a physiologically based pharmacokinetic\/pharmacodynamic (PBPK\/PD) model of dapagliflozin using curated data from 28 clinical studies. This framework integrates absorption, distribution, metabolism, excretion, and pharmacodynamics, and accounts for key determinants of variability including renal and hepatic function, and food effects. Results: The simulations reproduced dose-dependent pharmacokinetics with predicted Cmax and AUC values typically within 10\u201315% of observed data. Renal impairment reduced UGE by 40\u201360% despite modest changes in plasma exposure, while hepatic impairment produced only small shifts in PK and PD. The model also reproduced the fed-state reduction of peak concentrations, consistent with the 30\u201350% decrease reported clinically. Conclusions: All model files, code, and curated datasets are openly available in line with FAIR standards and Open Science practices, enabling transparent and reproducible analyses and providing a mechanistic basis for individualized therapy in type 2 diabetes.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030287","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK\/PD) Model of Dapagliflozin in Type 2 Diabetes Mellitus: The Effect of Dosing, Hepatorenal Impairment, and Food"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4892-3279","authenticated-orcid":false,"given":"Nike","family":"Nemitz","sequence":"first","affiliation":[{"name":"Faculty of Life Science, Institute for Biology, Systems Medicine of the Liver, Humboldt-Universit\u00e4t zu Berlin, Unter den Linden 6, 10099 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7959-3164","authenticated-orcid":false,"given":"Michelle","family":"Elias","sequence":"additional","affiliation":[{"name":"Faculty of Life Science, Institute for Biology, Systems Medicine of the Liver, Humboldt-Universit\u00e4t zu Berlin, Unter den Linden 6, 10099 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1725-179X","authenticated-orcid":false,"given":"Matthias","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Faculty of Life Science, Institute for Biology, Systems Medicine of the Liver, Humboldt-Universit\u00e4t zu Berlin, Unter den Linden 6, 10099 Berlin, Germany"},{"name":"Institute of Structural Mechanics and Dynamics in Aerospace Engineering, University of Stuttgart, Pfaffenwaldring 27, 70569 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00508-022-02122-y","article-title":"Diabetes mellitus: Definition, classification, diagnosis, screening and prevention (Update 2023)","volume":"135","author":"Harreiter","year":"2023","journal-title":"Wien. 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