The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation
The drug‐induced liver injury (DILI)‐sim Initiative is a public‐private partnership involving scientists from industry, academia, and the US Food and Drug Administration (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 hepatotoxicity 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 noncompetitive 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 nonimmune 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, in the future, it may be possible to use the DILIsym 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 DILI.
By Paul B Watkins