Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Abstract

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.

A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

“…Idiosyncratic DILI occurs unpredictably, with variable length latency and sometimes without dose-dependency563233. Interestingly, the PTGS classified idiosyncratic DILI-drugs in dose-dependent manners, for example, nimesulide (cf.…”

Species differences in bile acids II. Bile acid metabolism

“…A variety of in vitro models including membrane vesicles expressing BA transporters, primary hepatocytes and sandwich culture hepatocytes have been developed to support high‐throughput assessment of DILI risk (Atienzar et al, ). For example, inhibition of the bile salt export pump (BSEP), which facilitates the biliary excretion of BAs in the canaliculi and, more recently, other transporters such as the multidrug resistance‐association proteins, have been the focus as a primary mechanism and an in vitro screening tool for cholestatic DILI, and possibly DILI in general (Kock et al, ; Yucha et al, ).…”

Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease

“…107 Although considerable progress has been made in developing test systems for (cholestatic) DILI, in particular for elucidating the intrinsic toxicity of a drug, developing models for studying idiosyncratic toxicity remains challenging to date. 108 It should, however, also be kept in mind that so far no in vitro cell system modeling the liver and capable of generating bile flow is available, and it is likely that such an achievement will be very challenging. At the clinical level, search of susceptibility factors for DILI using genome-wide association studies with DILI 109 has lead, for example, to the identification of HLA class I and II alleles as susceptibility factors 110,111 and to the identification of genes coding for drug-metabolizing enzymes.…”