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The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial\u2010related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse\u2010specific version of the model to quantify doxorubicin and 5\u2010fluorouracil (5\u2010FU)\u2010induced toxicity, which included pharmacokinetics and 5\u2010FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose\u2010dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human\u2010specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5\u2010FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific\u2010molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug\u2010induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross\u2010settings differences in toxicity when building these approaches.<\/jats:p>","DOI":"10.1002\/psp4.13029","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T23:59:30Z","timestamp":1692921570000},"page":"1511-1528","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug\u2010induced toxicity"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1805-2357","authenticated-orcid":false,"given":"Louis","family":"Gall","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Jardi","sequence":"additional","affiliation":[{"name":"Preclinical Sciences &amp; Translational Safety Janssen Pharmaceutica NV  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieve","family":"Lammens","sequence":"additional","affiliation":[{"name":"Preclinical Sciences &amp; Translational Safety Janssen Pharmaceutica NV  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Pi\u00f1ero","sequence":"additional","affiliation":[{"name":"Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM) UPF  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terezinha M.","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Developmental Biology Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Developmental Biology Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8618-2487","authenticated-orcid":false,"given":"Danyel G. 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