Risk Of Idiosyncratic Drug-induced Liver Injury Research Articles

An original donor-dependent spheroid system for the prediction of idiosyncratic drug-induced liver injury risk

One major drawback of preclinical models to test drug-induced liver injury (DILI) is their inability to predict the interindividual difference of DILI effect in a population. Consequently, a high number of molecules that passed preclinical phases, fail clinical trials, and many FDA-approved drugs were removed from the market due to idiosyncratic DILI. We use a proprietary-depleted human serum-based cell educating technology to generate donor-dependent spheroids with distinct morphology and functionality. We demonstrate that educated spheroids could capture the large variations in susceptibility to drug-induced liver injury between donors. We show that the model could predict clinical apparent DILI risk with a high specificity and sensitivity. We provide evidence that the model could address non-genetic factor-associated DILI risk and severity such as age or sex. Our study supports the benefit of using donor-dependent educated spheroids for hepatotoxicity evaluation in preclinical phase or in an exploratory study clinical trial phase 2 to provide a robust safety profile to a drug.

Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk?

In vitro assays are commonly used during drug discovery to try to decrease the risk of idiosyncratic drug-induced liver injury (iDILI). But how effective are they at predicting risk? One of the most widely used methods evaluates cell cytotoxicity. Cytotoxicity assays that used cell lines that are very different from normal hepatocytes, and high concentrations of drug, were not very accurate at predicting idiosyncratic drug reaction risk. Even cytotoxicity assays that use more biologically normal cells resulted in many false-positive and false-negative results. Assays that quantify reactive metabolite formation, mitochondrial injury, and bile salt export pump (BSEP) inhibition have also been described. Although evidence suggests that reactive metabolite formation and BSEP inhibition can play a role in the mechanism of iDILI, these assays are not very accurate at predicting risk. In contrast, inhibition of the mitochondrial electron transport chain appears not to play an important role in the mechanism of iDILI, although other types of mitochondrial injury may do so. It is likely that there are many additional mechanisms by which drugs can cause iDILI. However, simply measuring more parameters is unlikely to provide better predictive assays unless those parameters are actually involved in the mechanism of iDILI. Hence, a better mechanistic understanding of iDILI is required; however, mechanistic studies of iDILI are very difficult. There is substantive evidence that most iDILI is immune mediated; therefore, the most accurate assays may involve those that determine immune responses to drugs. New methods to manipulate immune tolerance may greatly facilitate development of more suitable methods.

Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury

Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) – a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1−/− mice co-treated with anti-CTLA-4 antibodies. The PD-1−/− + anti-CTLA-4 model produces an immune-mediated liver injury very similar to the idiosyncratic liver injury observed in humans. The liver injury observed in the present experiment was dominated by the injury caused by the MCD diet; there was no significant difference between mice treated with the MCD diet alone and those also treated with AQ, whether in wild-type mice of the PD-1−/− model. Therefore, the MCD diet, which results in a state that mimics NASH, did not appear to increase the liver injury associated with AQ treatment. Ultimately, an animal model is just that – only a model, and cannot provide a definitive answer to clinical questions. However, given the difficulty of performing clinical studies with appropriate control populations, the present results provide important evidence to support a general clinical finding that underlying liver injury does not usually increase the risk of IDILI.