{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:42:29Z","timestamp":1792208549806,"version":"4.4.0"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"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":[[2026,11]]},"abstract":"<jats:p>\n                    Obeticholic acid (OCA), a synthetic analog of chenodeoxycholic acid, was approved in 2016 for the treatment of primary biliary cholangitis. Early clinical trials revealed elevated liver biomarkers in healthy subjects receiving supratherapeutic OCA doses (100\u2013250\u2009mg). OCA was also evaluated as a treatment for metabolic dysfunction\u2010associated steatotic liver disease (MASLD) but was not approved by the FDA due to liver safety concerns. In this\n                    <jats:italic>in silico<\/jats:italic>\n                    study, we investigated mechanisms of OCA\u2010associated liver injury in virtual healthy and MASLD populations receiving supratherapeutic and therapeutic (10\u201325\u2009mg) doses, respectively. OCA and metabolite exposures in plasma, sinusoidal blood, liver, and gut compartments were simulated using a physiologically based pharmacokinetic model. In the virtual MASLD population, exposures were increased 2\u2010, 5\u2010, and 10\u2010fold in plasma, sinusoidal, and\/or liver compartments relative to baseline. Mechanistic parameters relevant to OCA\u2010mediated liver injury, including bile acid transporter inhibition and mitochondrial dysfunction, were incorporated into the DILIsym model. Predicted liver injury was reported as evaluation of drug\u2010induced serious hepatotoxicity (eDISH) plots, and elevations in alanine aminotransferase, aspartate aminotransferase, and total hepatic bile acids. DILIsym simulations recapitulated liver biomarker elevations observed at supratherapeutic OCA doses in healthy subjects and predicted biomarker increases in the MASLD population under conditions of 5\u2010 and 10\u2010fold increased exposures relevant to this population. Bile acid transporter inhibition alone reproduced simulated biomarker elevations, whereas mitochondrial uncoupling alone predicted increased biomarkers only at the highest exposures. Results suggest that DILIsym modeling would have predicted the liver safety concerns that led to withdrawal of OCA from the US market.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70355","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:25:26Z","timestamp":1782185126000},"page":"1358-1367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Systems Toxicology Model Predicts Obeticholic Acid\u2010Associated Liver Injury in Metabolic Dysfunction\u2010Associated Steatotic Liver Disease"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0088-350X","authenticated-orcid":false,"given":"Abigail K.","family":"Mayo","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-8844","authenticated-orcid":false,"given":"James J.","family":"Beaudoin","sequence":"additional","affiliation":[{"name":"Quantitative Systems Pharmacology Solutions, Simulations Plus, Inc.  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3326-1210","authenticated-orcid":false,"given":"Jeffrey L.","family":"Woodhead","sequence":"additional","affiliation":[{"name":"Quantitative Systems Pharmacology Solutions, Simulations Plus, Inc.  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3343-4418","authenticated-orcid":false,"given":"Paul B.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L. R.","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S113052"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-016-0616-x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41395-018-0390-3"},{"key":"e_1_2_10_4_1","first-page":"2464","article-title":"Obeticholic acid for primary biliary cholangitis","volume":"10","author":"Floreani A.","year":"2022","journal-title":"Biomedicine"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldaa006"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm049904b"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12421"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.07.036"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21991"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-019-05398-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000037271"},{"key":"e_1_2_10_12_1","unstructured":"Clinical Pharmacology and Biopharmaceutics NDA Review and Evaluation Application Number: 207999Orig1s000 (U.S. Food and Drug Administration Center for Drug Evaluation and Research)(2016)."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31017"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.12.005"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509840"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15386"},{"key":"e_1_2_10_17_1","unstructured":"Intercept.Intercept Announces Voluntary Withdrawal of OCALIVA\u00ae for Primary Biliary Cholangitis (PBC) from the US Market; US Clinical Trials Involving Obeticholic Acid Placed on Clinical Hold. GLOBE NEWSWIRE<https:\/\/www.interceptpharma.com\/about\u2010us\/news\/?id=3148535>. Accessed 8 February 2026."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000004"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2024.0431"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000003355"},{"key":"e_1_2_10_21_1","first-page":"802","article-title":"Pipeline of new drug treatment for non\u2010alcoholic fatty liver disease\/metabolic dysfunction\u2010associated steatotic liver disease","volume":"12","author":"Hu Y.","year":"2024","journal-title":"J. Clin. Transl. 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