{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:50:55Z","timestamp":1791337855437,"version":"4.3.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031585","name":"Takeda Development Center Americas, Inc.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031585","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding. Hepatic liabilities were absent in rat and nonhuman primate safety studies, however, murine studies initiated during clinical trials revealed hepatic single-cell necrosis following cytochrome P450 induction at clinically relevant doses. Hepatic cell culture experiments uncovered wide margins to known mechanisms of intrinsic DILI, including cytotoxicity (&amp;gt;100\u00d7 Cmax\/IC50), mitochondrial toxicity (&amp;gt;100\u00d7 Cmax\/IC50), and bile salt efflux pump inhibition (&amp;gt;20\u00d7 Css, avg\/IC50). A potential covalent binding liability was uncovered with TAK-994 following hepatic metabolism consistent with idiosyncratic DILI and the delayed-onset clinical toxicity. Although idiosyncratic DILI is challenging to detect preclinically, reductions in total daily dose and covalent binding can reduce the covalent body binding burden and, subsequently, the clinical incidence of idiosyncratic DILI.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf003","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T16:50:37Z","timestamp":1736441437000},"page":"143-153","source":"Crossref","is-referenced-by-count":10,"title":["TAK-994 mechanistic investigation into drug-induced liver injury"],"prefix":"10.1093","volume":"204","author":[{"given":"Tadahiro","family":"Shinozawa","sequence":"first","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd , Fujisawa, Kanagawa 251-8555,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd , Fujisawa, Kanagawa 251-8555,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin S","family":"Baker","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha C","family":"Faber","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc , San Diego, CA 92121,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Flores","sequence":"additional","affiliation":[{"name":"Clarivate , 398 08025 Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Uetrecht","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto , Toronto, ON M5S 3M2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"von Hehn","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Yukawa","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd , Fujisawa, Kanagawa 251-8555,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7275-5790","authenticated-orcid":false,"given":"Kimio","family":"Tohyama","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd , Fujisawa, Kanagawa 251-8555,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harisha","family":"Kadali","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc , Cambridge, MA 02139,","place":["United 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An analysis using human hepatocytes and liver S-9 fraction","volume":"22","author":"Bauman","year":"2009","journal-title":"Chem Res Toxicol"},{"key":"2025032706250270300_kfaf003-B2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/toxsci\/kfx284","article-title":"Measures of BSEP inhibition in vitro are not useful predictors of DILI","volume":"162","author":"Chan","year":"2018","journal-title":"Toxicol Sci"},{"key":"2025032706250270300_kfaf003-B3","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0092-8674(00)81973-X","article-title":"Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation","volume":"98","author":"Chemelli","year":"1999","journal-title":"Cell"},{"key":"2025032706250270300_kfaf003-B4","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1002\/hep.28678","article-title":"A model to predict severity of drug-induced liver injury in 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