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Exposure occurred from initiation through 30\u2009days after discontinuation or up to 1 year. We measured age\u2010\/sex\u2010adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real\u2010world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90\u2009days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 89\u2009512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR\u2009=\u20092.17 [95% CI, 1.24\u20133.82]), but not pantoprazole (HR\u2009=\u20090.83 [95% CI, 0.61\u20131.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR\u2009=\u20091.99 [95% CI, 1.13\u20133.50]). Among 2\u2009462\u2009414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR\u2009=\u20091.66 [95% CI, 0.99\u20132.77]) but were significantly lower for pantoprazole (HR\u2009=\u20090.59 [95% CI, 0.37\u20130.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR\u2009=\u20091.52 [95% CI, 0.91\u20132.54]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pds.70069","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T01:29:21Z","timestamp":1733966961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hepatotoxicity Score: A New Method to Adjust for Use of Potentially Hepatotoxic Medications by Chronic Liver Disease Status"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-0600","authenticated-orcid":false,"suffix":"III","given":"Vincent","family":"Lo Re","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig W.","family":"Newcomb","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-270X","authenticated-orcid":false,"given":"Dean M.","family":"Carbonari","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa K.","family":"Mezochow","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Hennessy","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-7907","authenticated-orcid":false,"given":"Christopher T.","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Department of Non\u2010Communicable Disease Epidemiology London School of Hygiene &amp; Tropical Medicine  London UK"},{"name":"US Department of Veterans Affairs VA Connecticut Healthcare System  West Haven Connecticut USA"},{"name":"Department of Medicine Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley S.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet P.","family":"Tate","sequence":"additional","affiliation":[{"name":"US Department of Veterans Affairs VA Connecticut Healthcare System  West Haven Connecticut USA"},{"name":"Department of Medicine Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Br\u00e4u","sequence":"additional","affiliation":[{"name":"James J. 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