Predictable DILI

What are the key strategies in predicting DILI Most of the DILI are idiosyncratic, meaning that not all patients taking the drug will experience liver toxicity. In fact, only a small percentage of patients (typically fewer than 1 in 100) will experience elevated liver enzymes in their sera (a biomarker for liver injury), and even a smaller percentage (typically fewer than 1 in 1,000 patients) will go... 

DILI is divided by type of occurrence into predictable and idiosyncratic. Predictable DILI is the most common form and follows dose-response curves and is typically present in all patients during overdose. The archetypical example of predictable DILI is that of paracetamol hepato-toxicity and is the leading cause of acute liver failure in... 

In theory at least, the multi-hit hypothesis can explain the low incidence rate and idiosyncratic nature of DILI. Consider a simple scenario where a particular DILI requires three distinct steps or mechanisms, and the probability of each step occurring in a patient population is <10 percent (or less than 1 in 10 patients). Assuming that the probabilities of these three steps are completely independent of each other, then the overall probability of DILI becomes less than 1 in 1,000 patients. Since a combination of toxicity mechanisms may account for the final DILI, it is imperative that an integrated approach be developed and evaluated to better predict safer drugs. The remainder of this chapter will provide illustrations of such approaches. 

Previous efforts to develop in vitro methods and in silico tools, which enable production of fiver toxicity caused by drugs and chemicals, have been focused primarily upon evaluation of initiating direct chemical insults, rather than amplification processes or individual susceptibility factors. Approaches that appear to be particularly promising are outlined in the following, and their value for prediction of DILI is discussed. 

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