The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and develop
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REVIEW ARTICLE
The evolution of strategies to minimise the risk of human drug‑induced liver injury (DILI) in drug discovery and development Paul A. Walker1 · Stephanie Ryder1 · Andrea Lavado1 · Clive Dilworth1,2 · Robert J. Riley1 Received: 14 November 2019 / Accepted: 22 April 2020 © The Author(s) 2020
Abstract Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multiparametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated. Keywords Hepatotoxicity · Spheroid · HCI · DILI · Cmax.tot · Cmax,u · Strategies
Introduction Drug-induced liver injury (DILI) remains a leading cause of drug failure in terms of clinical trials and drug withdrawals (Watkins 2011; Cook et al. 2014). Approximately 18% of compound withdrawals from the market between 1953 and 2013 were due to hepatotoxicity, making the liver the most frequent site of adverse drug reactions (ADRs) leading to Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02763-w) contains supplementary material, which is available to authorized users. * Paul A. Walker [email protected] Stephanie Ryder [email protected] Andrea Lavado [email protected] Clive Dilworth [email protected] Robert J. Riley [email protected] 1
Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Present Address: Alderley Park Accelerator, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
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drug failure (Onakpoya et al. 2016). Significant inter-species differences in drug absorption, distribution, metabolism, and excretion (ADME), resulting in differences in metabolic fates and the exposure of test compounds in blood and key tissues (Martignoni et al. 2006), confound the extrapolation of data derived from pre-clinical species. Moreover, a large-scale comparison of animal versus human toxicity associated with 150 compounds found that rodent (primarily rat) and non-rodent (primarily dog) animal models predicted only approximately 50% of the human DILI events attributed to these drugs (Olson et al. 2000). More recent analyses have gone so far as to propose that the quality of preclinical safety profiles may actually be inversely correlated with clinical stage project closure due to safety issues (Cook et al. 2014). The pharmaceutical industry has responded to this chall
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