{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T18:37:38Z","timestamp":1779907058983,"version":"3.53.1"},"reference-count":96,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["R43TR003535"],"award-info":[{"award-number":["R43TR003535"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["R44TR003535"],"award-info":[{"award-number":["R44TR003535"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["5R01DK001881-04"],"award-info":[{"award-number":["5R01DK001881-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["5UH3DK119973-04"],"award-info":[{"award-number":["5UH3DK119973-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring. To evaluate the clinical risk of biologics-induced liver injury, a novel quantitative systems toxicology modeling platform, BIOLOGXsym\u2122, representing relevant liver biochemistry and the mechanistic effects of biologics on liver pathophysiology, was developed in conjunction with clinically relevant data from a human biomimetic liver microphysiology system. Phenotypic and mechanistic toxicity data and metabolomics analysis from the Liver Acinus Microphysiology System showed that tocilizumab and GGF2 increased high mobility group box 1, indicating hepatic injury and stress. Tocilizumab exposure was associated with increased oxidative stress and extracellular\/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals.<\/jats:p>","DOI":"10.3390\/ijms24119692","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T10:08:41Z","timestamp":1685700521000},"page":"9692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-8844","authenticated-orcid":false,"given":"James J.","family":"Beaudoin","sequence":"first","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Clemens","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Miedel","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6456-0195","authenticated-orcid":false,"given":"Albert","family":"Gough","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Metabolon Inc., Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Ramamoorthy","sequence":"additional","affiliation":[{"name":"Metabolon Inc., Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari E.","family":"Wong","sequence":"additional","affiliation":[{"name":"Metabolon Inc., Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rangaprasad","family":"Sarangarajan","sequence":"additional","affiliation":[{"name":"Metabolon Inc., Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-0208","authenticated-orcid":false,"given":"Christina","family":"Battista","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisl K. M.","family":"Shoda","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott Q.","family":"Siler","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Lansing","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett A.","family":"Howell","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-3167","authenticated-orcid":false,"given":"Lawrence A.","family":"Vernetti","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyunghee","family":"Yang","sequence":"additional","affiliation":[{"name":"DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","unstructured":"FDA (2018). 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