MIP-DILI · Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury

The current test systems employed by Industry are poorly predictive for Drug induced liver injury (DILI). The ‘MIP-DILI’ project will address this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis will be adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. The approach will encompass completely characterised cell lines, well-defined and physiologically stable hepatocytes, multi-cell type in vitro models including novel bioreactors, animal models and appropriate ex vivo human cell models. A systematic analysis of data and iteration at each stage will select the ‘best’ cell line, animal model or pathway for further investigation moving from simple systems to more complex models with reference to relevant clinical and preclinical data on the various forms of DILI. Triangulation of human, in vitro and animal data will provide a fundamental understanding of how drugs can harm the liver. It will then be possible to define the application of each particular novel test system in the context of drug development, and its use in the prediction of liabilities associated with the various forms of DILI that occur in man. Just as importantly, the project will define those models that are not appropriate as decision-making tools for the prediction of DILI in man.The MIP-DILI consortium contains Key Opinion Leaders from academia, the biotechnology sector and the pharmaceutical industry in the fields of drug development, drug metabolism, drug toxicology, drug hypersensitivity, liver immunology, liver cell biology, pharmacogenetics, systems biology and clinical adverse drug reactions.