Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury

ABSTRACT

Introduction: The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development.

Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted.

Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

KEYWORDS:

• Human
• hepatocytes
• HepaRG
• HepG2
• DILI
• liver
• drug discovery
• drug development
• hepatobiliary
• cytotoxicity
• mitochondrial toxicity
• cholestasis
• immune system
• IMI
• test systems
• endpoints

Article Highlights

• No standard approach exists in the pharmaceutical industry with respect to the systematic and sequential use of in vitro test systems for detection of human DILI

• Of the numerous tests for DILI, a first screen for the detection of cytotoxicity is broadly adopted across the industry

• No test systems have been robustly evaluated for performance and bench-marked across the industry

• A consensus among EFPIA members identifies several major gaps for improvement for the detection of DILI

• Greater Industry consensus is likely only achievable with systematic evidence-based pharmacological and physiological characterization of routinely used hepatocellular-based cell models and endpoints fit for decision-making in Drug Discovery

• Better understanding of DILI will lead to better, predictive in vitro tools in the future

• 3D microphysiological cell models are exciting, but still require characterization and validation for acceptance and application within EFPIA companies

This Box summarizes key points contained in this article.

Declaration of interest

European Federation of Pharmaceutical Industries and Associations companies (EFPIA) contributing to the preparation of the paper, but which did not provide financial support are AbbVie (E Bloome, M Ligouri),, AstraZeneca (C Betts, M Ogese, M Persson), GlaxoSmithKline (T Walker), Lilly (J Stevens), Janssen (J Snoeys, N Messens), Lundbeck (K Gjervig), Merck (P Hewitt), Orion (S Juhila). Sanofi (G Labbes), Servier (R Weaver), UCB BioPharma (H Gerets). Brain Kevin Park received funding from the European Community under the Innovative Medicines Intiative (IMI) Programme through Grant agreement number 115,335. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper is funded by the Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP-DILI) consortium. The academic body in receipt of financial support is University of Liverpool, UK (Kevin Park). The MIP-DILI consortium is supported by the Innovative Medicines Initiative Grant Agreement Number 115336