{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:09:04Z","timestamp":1792786144876,"version":"4.5.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Biohaven, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant\u2019s failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac051","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:01:58Z","timestamp":1651795318000},"page":"108-116","source":"Crossref","is-referenced-by-count":52,"title":["Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling"],"prefix":"10.1093","volume":"188","author":[{"given":"Jeffrey L","family":"Woodhead","sequence":"first","affiliation":[{"name":"DILIsym Services, Inc., A Simulations Plus Company , Research Triangle Park, North Carolina 27706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott Q","family":"Siler","sequence":"additional","affiliation":[{"name":"DILIsym Services, Inc., A Simulations Plus Company , Research Triangle Park, North Carolina 27706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett A","family":"Howell","sequence":"additional","affiliation":[{"name":"DILIsym Services, Inc., A Simulations Plus Company , Research Triangle Park, North Carolina 27706, USA"}],"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":"Institute for Drug Safety Sciences, UNC-Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Conway","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals, Inc. , New Haven, Connecticut 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"2022062811293080900_kfac051-B1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1474-4422(21)00409-9","article-title":"Calcitonin gene-related peptide-targeting drugs for migraine: How pharmacology might inform treatment decisions","volume":"21","author":"Al-Hassany","year":"2022","journal-title":"Lancet Neurol"},{"key":"2022062811293080900_kfac051-B2","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1111\/head.13930","article-title":"Safety of rimegepant, an oral CGRP receptor antagonist, plus CGRP monoclonal antibodies for migraine","volume":"60","author":"Berman","year":"2020","journal-title":"Headache"},{"key":"2022062811293080900_kfac051-B3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/head.13305","article-title":"The CGRP pathway in migraine as a viable target for therapies","volume":"58(Suppl 1)","author":"Edvinsson","year":"2018","journal-title":"Headache"},{"key":"2022062811293080900_kfac051-B4","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S1474-4422(20)30234-9","article-title":"Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: A double-blind, randomised phase 2b\/3 trial","volume":"19","author":"Goadsby","year":"2020","journal-title":"Lancet Neurol"},{"key":"2022062811293080900_kfac051-B5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1753-5174.2010.00031.x","article-title":"The dose proportionality of telcagepant after administration of single oral and intravenous doses in healthy adult subjects","volume":"3","author":"Han","year":"2010","journal-title":"Arch. Drug Inf"},{"key":"2022062811293080900_kfac051-B6","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1177\/0333102411398399","article-title":"Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine","volume":"31","author":"Hewitt","year":"2011","journal-title":"Cephalalgia"},{"key":"2022062811293080900_kfac051-B7","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1177\/0333102415584308","article-title":"Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine","volume":"36","author":"Ho","year":"2016","journal-title":"Cephalalgia"},{"key":"2022062811293080900_kfac051-B8","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s13311-018-0617-4","article-title":"Targeted CGRP small molecule antagonists for acute migraine therapy","volume":"15","author":"Holland","year":"2018","journal-title":"Neurotherapeutics"},{"key":"2022062811293080900_kfac051-B9","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1093\/toxsci\/kfy253","article-title":"Quantitative systems toxicology analysis of in vitro mechanistic assays reveals importance of bile acid accumulation and mitochondrial dysfunction in TAK-875-induced liver injury","volume":"167","author":"Longo","year":"2019","journal-title":"Toxicol. Sci."},{"key":"2022062811293080900_kfac051-B10","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/psp4.12053","article-title":"Elucidating differences in the hepatotoxic potential of tolcapone and entacapone with DILIsym(\u00ae), a mechanistic model of drug-induced liver injury","volume":"5","author":"Longo","year":"2016","journal-title":"CPT Pharmacometrics Syst. Pharmacol"},{"key":"2022062811293080900_kfac051-B11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1097\/WCO.0000000000000806","article-title":"Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment?","volume":"33","author":"Moreno-Ajona","year":"2020","journal-title":"Curr. Opin. Neurol"},{"key":"2022062811293080900_kfac051-B12","doi-asserted-by":"crossref","first-page":"e2121","DOI":"10.1212\/WNL.0000000000008944","article-title":"Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy","volume":"94","author":"Mullin","year":"2020","journal-title":"Neurology"},{"key":"2022062811293080900_kfac051-B13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cotox.2020.06.003","article-title":"DILIsym: Quantitative systems toxicology impacting drug development","volume":"23-24","author":"Watkins","year":"2020","journal-title":"Curr. Opin. Toxicol"},{"key":"2022062811293080900_kfac051-B14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/toxsci\/kfw193","article-title":"Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors","volume":"155","author":"Woodhead","year":"2017","journal-title":"Toxicol. Sci."},{"key":"2022062811293080900_kfac051-B15","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s11095-019-2726-0","article-title":"Comparison of the hepatotoxic potential of two treatments for autosomal-dominant polycystic kidney disease using quantitative systems toxicology modeling","volume":"37","author":"Woodhead","year":"2020","journal-title":"Pharm. Res"},{"key":"2022062811293080900_kfac051-B16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s11095-019-2582-y","article-title":"Analyzing the mechanisms behind macrolide antibiotic-induced liver injury using quantitative systems toxicology modeling","volume":"36","author":"Woodhead","year":"2019","journal-title":"Pharm. Res"},{"key":"2022062811293080900_kfac051-B17","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3389\/fphar.2014.00240","article-title":"Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury","volume":"5","author":"Woodhead","year":"2014","journal-title":"Front. Pharmacol"},{"key":"2022062811293080900_kfac051-B18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.taap.2013.01.018","article-title":"Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats","volume":"268","author":"Yamazaki","year":"2013","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2022062811293080900_kfac051-B19","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1007\/s11095-014-1591-0","article-title":"MITOsym\u00ae: A mechanistic, mathematical model of hepatocellular respiration and bioenergetics","volume":"32","author":"Yang","year":"2014","journal-title":"Pharm. Res"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfac051\/43814972\/kfac051.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/188\/1\/108\/44272624\/kfac051.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/188\/1\/108\/44272624\/kfac051.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T07:30:33Z","timestamp":1656401433000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/188\/1\/108\/6584837"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,5,12]]},"published-print":{"date-parts":[[2022,6,28]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfac051","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,7,1]]},"published":{"date-parts":[[2022,5,12]]}}}