{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:50:38Z","timestamp":1786114238926,"version":"build-2736575974"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Plasma 4\u03b2\u2010hydroxycholesterol (4\u03b2\u2010OHC) normalized for the levels of its parent cholesterol (4\u03b2\u2010OHC\/C) is an endogenous biomarker for hepatic CYP3A4. This study evaluated CYP3A4 activity longitudinally in individuals while their obesity status was changing. 4\u03b2\u2010OHC\/C was measured pre\u2010surgery (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200954) and 2\u2009years after Roux\u2010en\u2010Y gastric bypass (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930) and used as an input for creating virtual twins of each patient within physiologically\u2010based pharmacokinetic (VT\u2010PBPK) models, alongside other available data (e.g., demographics). Additionally, individual CYP3A4 abundance quantified from liver biopsies during surgery was available. Predicted CYP3A4 abundance using 4\u03b2\u2010OHC\/C was within twofold of the measured abundance in 85% of the individuals (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200954). Pre\u2010surgery VT\u2010PBPK models informed by biomarker data predicted area under curve after intravenous midazolam (AUC\n                    <jats:sub>inf,iv<\/jats:sub>\n                    ) within twofold of observed values in 85% of individuals (geometric mean fold error (GMFE)\u2009=\u20091.58). VT\u2010PBPK models using CYP3A4 protein measurements showed similar performance (83% within twofold, GMFE\u2009=\u20091.66), verifying the biomarker approach. The post\u2010surgery VT\u2010PBPK models were revised to reflect surgery\u2010related alterations and changes in obesity status. Hepatic CYP3A4 activity at 2\u2009years was predicted from 4\u03b2\u2010OHC\/C measured in the same individuals. Biomarker\u2010informed models predicted midazolam AUC\n                    <jats:sub>inf,iv<\/jats:sub>\n                    within twofold for 87% of individuals (GMFE\u2009=\u20091.48;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930). ~60% of observed oral midazolam PK parameters were predicted within twofold, improving to 70% when the surgery model assumed full intestinal CYP3A4\/5 recovery. This study highlights the utility of 4\u03b2\u2010OHC\/C for continuous monitoring of CYP3A4 activity and possibility to use biomarker\u2010informed VT\u2010PBPK models for individual dose requirements of intravenously administered CYP3A substrates in individuals with obesity over the course of weight loss treatment.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70369","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T06:48:03Z","timestamp":1781851683000},"page":"762-773","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Application of Virtual Twin PBPK Models in Individuals with Obesity via CYP3A4 Phenotyping Using Endogenous Biomarker Data"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7378-9100","authenticated-orcid":false,"given":"Nihan","family":"Izat","sequence":"first","affiliation":[{"name":"Centre for Applied Pharmacokinetic 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