{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:49:45Z","timestamp":1784231385531,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Cystic fibrosis (CF) is a chronic hereditary disease that affects tens of thousands of people worldwide. The introduction of CFTR modulator therapies such as elexacaftor\/tezacaftor\/ivacaftor (ETI) has significantly improved the quality of life of people with CF. However, ETI has been shown in clinical trials to cause elevations in liver enzymes, and real\u2010world cases of drug\u2010induced liver injury (DILI) have also been reported. The mechanism of ETI\u2010mediated DILI is currently unknown, hindering the development of more effective mitigation strategies for this adverse reaction. Through\n                    <jats:italic>in vitro<\/jats:italic>\n                    assays and quantitative systems toxicology modeling using DILIsym, this study revealed that ivacaftor contributed most significantly to ETI\u2010mediated DILI, primarily via reactive oxygen species production, resulting in mitochondrial dysfunction due to electron transport chain inhibition. DILIsym modeling also predicted liver enzyme elevations following daily dosing of ETI at a comparable frequency (6.0%) to that of clinical data (8.0%). Simulations of the therapeutic effects of DILI mitigation strategies for ETI showed that dose reduction and antioxidant administration may significantly reduce the frequency of liver enzyme elevations due to ETI.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70073","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T10:22:40Z","timestamp":1758622960000},"page":"208-218","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Quantitative Systems Toxicology Predicts Ivacaftor\u2010Induced Oxidative Stress Contributes to\n                    <scp>CFTR<\/scp>\n                    Modulator Hepatotoxicity"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6939-039X","authenticated-orcid":false,"given":"Alan","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole","family":"Cornwell","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7009-0944","authenticated-orcid":false,"given":"Kyunghee","family":"Yang","sequence":"additional","affiliation":[{"name":"Quantitative Systems Pharmacology Solutions Simulations Plus Inc.  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3744-3310","authenticated-orcid":false,"given":"Paul M.","family":"Beringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California  Los Angeles California USA"},{"name":"USC Anton Yelchin CF Clinic  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.8120"},{"key":"e_1_2_10_2_1","volume-title":"Patient Registry Annual Data Report","author":"Marshall B.","year":"2021"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908639"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32597-8"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00454-9"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2100665"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202102-0509OC"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202202-0392OC"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","unstructured":"Sharma P.&Giddings O.K.Acute Liver Failure in a Patient with Cystic Fibrosis Taking Triple Combination Modulator. Challenging Cases in Patients with Bronchiectasis. American Thoracic Society International Conference Abstracts: American Thoracic Society; p.\u00a0A2113\u2010A(2021).","DOI":"10.1164\/ajrccm-conference.2021.203.1_MeetingAbstracts.A2113"},{"key":"e_1_2_10_10_1","article-title":"Delayed hepatic necrosis in a cystic fibrosis patient taking elexacaftor\/tezacaftor\/ivacaftor (Kaftrio)","volume":"34","author":"Salehi M.","year":"2021","journal-title":"Respir. Med. Case. Rep."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2021.05.008"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2024.01.001"},{"key":"e_1_2_10_13_1","first-page":"73","article-title":"Drug\u2010induced liver injury","volume":"6","author":"David S.","year":"2010","journal-title":"US Gastroenterol. Hepatol. Rev."},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0105-0"},{"key":"e_1_2_10_15_1","volume-title":"Trikafta: Highlights of Prescribing Information","year":"2024"},{"key":"e_1_2_10_16_1","volume-title":"LiverTox: Clinical and Research Information on Drug\u2010Induced Liver Injury [Internet]","author":"Hoofnagle J.H.","year":"2021"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.074369"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx194"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaa019"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-019-2582-y"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","DOI":"10.1177\/1177625017696074","article-title":"Mechanistic modelling of drug\u2010induced liver injury: investigating the role of innate immune responses","volume":"11","author":"Shoda L.K.","year":"2017","journal-title":"Gene Regul. Syst. Biol."},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2016.11.008"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw193"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaa093"},{"key":"e_1_2_10_25_1","unstructured":"Yang K. Battista C. Woodhead J.L.&Watkins P.B.Quantitative systems toxicology modeling using DILIsym suggests that drug\u2010induced liver injury can be enhanced by co\u2010administered drugs and mitigated by mitochondrial biogenesisAAPS Annual Meeting PharmSci 360; Ernest N. Morial Convention Center New Orleans LA United States America (2020)."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2024.2361027"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3136"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfac051"},{"key":"e_1_2_10_29_1","volume-title":"Alyftrek: Highlights of Prescribing Information","year":"2024"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2585"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-022-00791-8"},{"key":"e_1_2_10_32_1","volume-title":"Extract From the Clinical Evaluation Report for Lumacaftor\/Ivacaftor","year":"2015"},{"key":"e_1_2_10_33_1","volume-title":"Agilent Seahorse XF Cell Mito Stress Test Kit User Guide","author":"Agilent Technologies, Inc","year":"2024"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-012-9446-z"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12053"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00900.x"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-012-9266-0"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1591-0"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15194"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3004"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/15569520701212233"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.038968"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70073","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T10:36:55Z","timestamp":1767004615000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70073"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cpt.70073"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70073","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]},"assertion":[{"value":"2025-05-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}