Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that pre- scription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical hu- man in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional-FEDER (contract numbers: PI18/01804, PI19-00883, PT20/00127, UMA18-FEDERJA-194, PY18-3364, Spain) and grants of Consejería de Salud de Andalucía cofounded by FEDER (contract number: PEMP-0127-2020, Spain). M.V.P. holds a Sara Borrell (CD21/00198, Spain) research contract from ISCIII and Consejería de Salud de Andalucía. C.L.G. holds a Juan de la Cierva Incorporación (IJCI-2017-31466, Spain) research contract from Ministerio de Ciencia del Gobierno de España. SCReN and CIBERehd are funded by ISCIII (Spain). This publication is based upon work from COST Action “CA17112dProspective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu. The figures in this review were created with Biorender.com

Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional-FEDER (contract numbers: PI18/01804, PI19-00883, PT20/00127, 3714 Antonio Segovia-Zafra et al. UMA18-FEDERJA-194, PY18-3364, Spain) and grants of Consejeríaa de Salud de Andalucı ́a cofounded by FEDER (contractnumber: PEMP-0127-2020, Spain). M.V.P. holds a Sara Borrell (CD21/00198, Spain) research contract from ISCIII and Consejerí a de Salud de Andalucía. C.L.G. holds a Juan de la Cierva Incorporación (IJCI-2017-31466, Spain) research contract from Ministerio de Ciencia del Gobierno de España. SCReN and CIBERehd are funded by ISCIII (Spain). This publication is based upon work from COST Action “CA17112dProspective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology)Ye