The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

Abstract

The DILI‐sim Initiative is a public‐private partnership involving scientists from industry, academia and the FDA. The Initiative uses Quantitative Systems Toxicology (QST) to build and refine a model (DILIsym^®) capable of understanding and predicting liver safety liabilities in new drug candidates and to optimize interpretation of liver safety biomarkers used in clinical studies. Insights gained to date include the observation that most dose‐dependent hepatoxicity can be accounted for by combinations of just three mechanisms (oxidative stress, interference with mitochondrial respiration, and alterations in bile acid homeostasis) and the importance of non‐competitive inhibition of bile acid transporters. The effort has also provided novel insight into species and interpatient differences in susceptibility, structure:activity relationships, and the role of non‐immune mechanisms in delayed idiosyncratic hepatotoxicity. The model is increasingly used to evaluate new drug candidates and several clinical trials are underway that will test the model's ability to prospectively predict liver safety. With more refinement it may in the future be possible to use the DILsym predictions to justify reduction in the size of some clinical trials. The mature model could also potentially assist physicians in managing the liver safety of their patients as well as aid in the diagnosis of drug‐induced liver injury.

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