{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:52:17Z","timestamp":1793386337044,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007819","name":"Allergan plc","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000\u2009mg (10-fold higher than the approved clinical dose of 100\u2009mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa093","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T03:30:44Z","timestamp":1592278244000},"page":"84-93","source":"Crossref","is-referenced-by-count":29,"title":["Mechanistic Investigations Support Liver Safety of Ubrogepant"],"prefix":"10.1093","volume":"177","author":[{"given":"Brenda","family":"Smith","sequence":"first","affiliation":[{"name":"Allergan plc, Irvine, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-2926","authenticated-orcid":false,"given":"Josh","family":"Rowe","sequence":"additional","affiliation":[{"name":"Allergan plc, Irvine, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-8917","authenticated-orcid":false,"given":"Paul B","family":"Watkins","sequence":"additional","affiliation":[{"name":"Eshelman School of Pharmacy and Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Messoud","family":"Ashina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Faculty of Health and Medical Sciences, University of Copenhagen, K\u00f8benhavn, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L","family":"Woodhead","sequence":"additional","affiliation":[{"name":"DILIsym Services, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank D","family":"Sistare","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Goadsby","sequence":"additional","affiliation":[{"name":"NIHR-Wellcome Trust King\u2019s Clinical Research Facility, SLaM Biomedical Research Centre, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"2020101315045568300_kfaa093-B1","first-page":"009","article-title":"Long-term safety evaluation of ubrogepant for the acute treatment of migraine [abstract]","volume":"92(Suppl. 15","author":"Ailani","year":"2019","journal-title":"Neurology"},{"key":"2020101315045568300_kfaa093-B2","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1177\/1535370217740853","article-title":"In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials","volume":"243","author":"Church","year":"2018","journal-title":"Exp. 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