Mechanism-based drug safety testing using innovative <i>in vitro</i> liver models: from DILI prediction to idiosyncratic DILI liability assessment

Idiosyncratic drug-induced liver injury (iDILI) remains unpredictable. As adverse responses arise in a small fraction of patients, drugs often fail in later drug development stages or post-approval, thereby tremendously increasing costs and putting patients at risk, highlighting the need for accurate early identification of iDILI liabilities. Using articles from the last 5 years (PubMed), iDILI risk factors are described, <i>in vitro</i> liver models and mechanism-based readout strategies are evaluated on their potential to enable iDILI liability assessment. Various <i>in vitro</i> liver models are established for disease modeling and DILI prediction. Drawbacks for each of these seem inevitable, making the evaluation of their application domain and iDILI liability assessment potential crucial. A tiered approach could be considered, whereby compounds are initially screened and flagged using simple fit-for-purpose models for DILI prediction, followed by multicellular liver models that integrate the current knowledge of iDILI onset in combination with mechanistic readouts. Multiplexing models within an integrated mechanism-based testing strategy could improve the safety assessment accuracy. Defined <i>in vitro</i> models should integrate critical hepatocyte intrinsic risk factors as well as adaptive immune system components to refine iDILI liability assessment.