The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development

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 multi-parametric 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: Cmax,u; Cmax.tot; DILI; HCI; Hepatotoxicity; Spheroid; Strategies.

Fig. 1

Distribution of assigned DILI categories and C_max.tot values and across 10 literature references for 33 compounds. C_max.tot (µM) values are plotted on a log scale when available in the literature. Green shading highlights compounds with negative DILI potential concordance, yellow shading highlights compounds of ambiguous DILI categorisation, red shading highlights compounds with positive DILI potential concordance across the literature. In vivo DILI potential ( +) and no DILI potential (−) are assigned from the literature, aligned with the DILI severity category (top; Chen et al. 2016), unless not available NA (color figure online)

Fig. 2

a Global comparison of therapeutic index (TI) for hLiMT’s with hepaRG spheroids for 54 compounds, assigned DILI severity categories taken from Chen et al. (2016) when available otherwise average literature category used. HepaRG spheroids plotted on the y-axis and hLiMT’s plotted on the x-axis. b Comparison of therapeutic index (TI) for high-content screening (HCS) endpoints alone with cellular ATP alone in hLiMTs c Comparison of therapeutic index (TI) for high-content screening (HCS) endpoints alone with cellular ATP alone in HepaRG spheroids. Open circle, most DILI severity; open square, less DILI severity; cross, no/ambiguous DILI severity. Axis crossing set at 25 to represent a 25 × C_max.tot cut-off. MEC < 25 × C_max.tot cut-off applied for DILI severity categories (color figure online)

Fig. 3

Correlation of hLiMT and hepaRG spheroid minimal effective concentration (MEC) of the first responding feature (µM) with either a plasma C_max.tot (µM) or b C_max,u (µM). Assigned DILI potential categories are taken from Chen et al. (2016) when available otherwise average literature category used. Squares are hepaRG spheroids and circles are hLiMTs, severe DILI potential; closed squares or circles, less DILI potential; grey squares or circles and no/ambiguous DILI potential; open squares or circles. Dashed line represents an MEC < 25 × C_max.tot or 100 × C_max,u cut-off. Solid black line represents 1 × C_max.tot or C_max,u. Red shading highlights area of positive DILI potential. Non-responding compounds assigned an arbitrary value of 20,000 µM (color figure online)