Modelling organ system toxicity
In most cases, market withdrawals of drugs or drug development terminations are due to liver and cardiovascular toxicity. Adverse effects can be detected even during late phases of clinical testing, or years after a drug has been introduced into the market. To prevent side effects and minimise the socioeconomic burden, we need effective tools to predict toxicity. The EU-funded HECATOS (Hepatic and cardiac toxicity systems modelling) project proposes to develop an in silico framework capable of modelling toxic perturbations in the liver and heart. This tool will integrate representations from drug-target interactions, systems toxicology and organ physiologies. Using advanced molecular and functional analytical techniques, the consortium will obtain data on key cellular toxic events and incorporate it into the model. They will also test various toxic compounds on novel in vitro 3D liver and heart assays. Given the role of mitochondrial deregulations and immunological dysfunctions in various hepatic and cardiac drug-induced injuries, focus is on these particular pathways. Input will also be provided from drug-treated patients and biopsy analyses using transcriptome and proteomic profiling. Comparison of in silico predictions with experimental results across a multitude of read-out parameters will validate the toxicity model and suggest further improvements. Such an in silico approach undoubtedly offers a number of advantages over existing animal-based models for predicting drug toxicity. It should become an indispensable tool for the pharmaceutical industry that could also be applied for safety assessment of industrial chemicals and cosmetic products.
Keywords
Toxicity, model, drug, in silico, liver, heart
