Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man.

Sanja Dragovic,Satu Juhila,Richard J. Weaver,Helga H. Gerets,B. Kevin Park,Magnus Ingelman‐Sundberg,Nico P. E. Vermeulen,Philip G. Hewitt,Jan Snoeys

doi:10.1007/s00204-016-1845-1

Abstract

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.

Highlights

The appropriate selection of compounds for use in the evaluation of existing and novel model systems for the improved, and mechanism-based prediction of drug-induced liver injury (DILI) in man requires special attention to overarching goals and strategies of the research programme
We focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI
This paper describes the selection and compilation of known human DILI mechanisms on the set of training compounds identified for use in MIP-DILI

Summary

Introduction

The appropriate selection of compounds for use in the evaluation of existing and novel model systems for the improved, and mechanism-based prediction of DILI in man requires special attention to overarching goals and strategies of the research programme. Non-parenchymal cells may be targets in DILI with the activation of the immune system and subsequent idiosyncratic reactions in which human leucocyte antigen (HLA) genotypes are implicated in the aetiology of these types of liver injury Consideration of these mechanisms of DILI forms the basis for the selection of a training set of compounds based on clinical pathology of liver injury, but where the actual mechanism of DILI remains to be better defined. While drugs are central to the mechanism-based selection of training compounds involved in liver injury, non-drugs such as rotenone may be valuable as reagents for use in demonstrating the relevance of in vitro models for the prediction of DILI in man, with respect to understanding specific molecular initiating events and molecular pathways leading to DILI. For details on the relevant processes and mechanisms involved in DILI of all training compound, reference is made to Table 5

Biliary

Findings

Summary and conclusions