Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Abstract

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

Pharmacokinetic Imaging Using 99mTc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats

“…This suggests that liver excretion of MRP2/3 substrates may be hindered, while uptake transport remains active during concomitant rifampicin therapy. This may lead to liver accumulation of concomitant drugs and bile acids, and account for the rifampicin-associated DILI observed in clinical practice [33,34].…”

In Vitro Models for Studying Chronic Drug-Induced Liver Injury

“…There is an urgent need of human-relevant in vitro models for preclinical testing during drug development processes. Although single-cell-type 2D cultures are still the most used for hepatotoxicity assessments [ 85 ], DILI is a complex process in which different cell types may be involved. Additionally, these systems usually cannot be cultured over long periods, thus limiting the study of chronic effects.…”

Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix

“…DILI is also the most common cause of a drug’s withdrawal from the market and restriction of use [ 12 ]. The failure to detect DILI during the drug development process is attributable to the poor predictability of the screening methods (in vitro, in vivo, ex vivo, and in silico) used in the preclinical phase [ 9 , 11 , 13 , 14 ].…”