A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity

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• dc.contributor.author Gall, Louis
• dc.contributor.author Jardí Pujol, Ferran
• dc.contributor.author Lammens, Lieve
• dc.contributor.author Piñero González, Janet, 1977-
• dc.contributor.author Souza, Terezinha
• dc.contributor.author Rodrigues, Daniela
• dc.contributor.author Jennen, Danyel
• dc.contributor.author de Kok, Theo M.
• dc.contributor.author Coyle, Luke
• dc.contributor.author Chung, Seung-Wook
• dc.contributor.author Ferreira, Sofia
• dc.contributor.author Jo, Heeseung
• dc.contributor.author Beattie, Kylie A.
• dc.contributor.author Kelly, Colette
• dc.contributor.author Duckworth, Carrie A.
• dc.contributor.author Pritchard, Mark
• dc.contributor.author Pin, Carmen
• dc.date.accessioned 2024-05-07T06:58:26Z
• dc.date.available 2024-05-07T06:58:26Z
• dc.date.issued 2023
• dc.description.abstract We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic-induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial-related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse-specific version of the model to quantify doxorubicin and 5-fluorouracil (5-FU)-induced toxicity, which included pharmacokinetics and 5-FU 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-dependent 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-specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5-FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific-molecularly 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-induced 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-settings differences in toxicity when building these approaches.
• dc.description.sponsorship The authors acknowledge financial support from TransQST consortium. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116030. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gall L, Jardi F, Lammens L, Piñero J, Souza TM, Rodrigues D, et al. A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity. CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1511-28. DOI: 10.1002/psp4.13029
• dc.identifier.doi http://dx.doi.org/10.1002/psp4.13029
• dc.identifier.issn 2163-8306
• dc.identifier.uri http://hdl.handle.net/10230/60051
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1511-28
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/116030
• dc.rights © 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.other Epiteli
• dc.subject.other Intestí prim
• dc.title A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion