{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:58:10Z","timestamp":1791903490052,"version":"4.3.4"},"reference-count":22,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>BAY1128688 is a selective inhibitor of AKR1C3, investigated recently in a trial that was prematurely terminated due to drug\u2010induced liver injury. These unexpected observations prompted use of the quantitative systems toxicology model, DILIsym, to determine possible mechanisms of hepatotoxicity. Using mechanistic <jats:italic>in vitro<\/jats:italic> toxicity data as well as clinical exposure data, DILIsym predicted the potential for BAY1128688 to cause liver toxicity (elevations in serum alanine aminotransferase (ALT)) and elevations in serum bilirubin. Initial simulations overpredicted hepatotoxicity and bilirubin elevations, so the BAY1128688 representation within DILIsym underwent optimization. The liver partition coefficient <jats:italic>K<\/jats:italic><jats:sub>p<\/jats:sub> was altered to align simulated bilirubin elevations with those observed clinically. Altering the mode of bile acid canalicular and basolateral efflux inhibition was necessary to accurately predict ALT elevations. Optimization results support that bilirubin elevations observed early during treatment are due to altered bilirubin metabolism and transporter inhibition, which is independent of liver injury. The modeling further supports that on\u2010treatment ALT elevations result from inhibition of bile acid transporters, particularly the bile salt excretory pump, leading to accumulation of toxic bile acids. The predicted dose\u2010dependent intrinsic hepatotoxicity may increase patient susceptibility to an adaptive immune response, accounting for ALT elevations observed after completion of treatment. These BAY1128688 simulations provide insight into the mechanisms behind hepatotoxicity and bilirubin elevations and may inform the potential risk posed by future compounds.<\/jats:p>","DOI":"10.1002\/cpt.3010","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T07:54:47Z","timestamp":1690530887000},"page":"1023-1032","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Quantitative Systems Toxicology Identifies Independent Mechanisms for Hepatotoxicity and Bilirubin Elevations Due to <scp>AKR1C3<\/scp> Inhibitor <scp>BAY1128688<\/scp>"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-0208","authenticated-orcid":false,"given":"Christina","family":"Battista","sequence":"first","affiliation":[{"name":"DILIsym Services division Simulations Plus, Inc.  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisl K.M.","family":"Shoda","sequence":"additional","affiliation":[{"name":"DILIsym Services division Simulations Plus, Inc.  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Eshelman School of Pharmacy Institute for Drug Safety Sciences University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Groettrup\u2010Wolfers","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Division Pharmacovigilance Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Rottmann","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Division Research &amp; Early Development Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Raschke","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Division Research &amp; Early Development Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant T.","family":"Generaux","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268\u2010023\u201000427\u20105"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2010.11.004"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2018.07.002"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/ejendo\/lvad063"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.58"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2016.11.008"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2020.104788"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2019.09.003"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2014.21"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1591-0"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.619"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaa093"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12180"},{"key":"e_1_2_10_14_1","unstructured":"Lukacova V. Parrott N. Lave T. Fraczkiewicz G. Bolger M.&Woltosz W.General approach to calculation of tissue: plasma partition coefficients for physiologically based pharmacokinetic (PBPK) modeling. Poster Presented at: 2008 AAPS National Annual Meeting and Exposition; Atlanta Georgia USA (November 16 2008)."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.1878"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00240"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-019-2582-y"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12053"},{"key":"e_1_2_10_19_1","unstructured":"Promega Corporation.ROS\u2010Glo\u2122 H2O2assay quick protocol. Instruction for Use of Products: G8820 and G8821. <https:\/\/www.promega.de\/\u2010\/media\/files\/resources\/protcards\/ros\u2010glo\u2010h2o2\u2010assay\u2010quick\u2010protocol.pdf?la=en> (2013). Accessed July 16 2021."},{"key":"e_1_2_10_20_1","unstructured":"Promega Corporation.Technical bulletin. CellTiter\u2010Glo\u00ae luminescent cell viability assay. Instructions for Use of Products: G7570 G7571 G7572 and G7573 <https:\/\/ch.promega.com\/\u2010\/media\/files\/resources\/protocols\/technical\u2010bulletins\/0\/celltiter\u2010glo\u2010luminescent\u2010cell\u2010viability\u2010assay\u2010protocol.pdf> (2015). Accessed July 16 2021."},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1222"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.564"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3010","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T06:51:23Z","timestamp":1702450283000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":22,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/cpt.3010"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3010","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]},"assertion":[{"value":"2023-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}