Human primary hepatic spheroids are scalable advanced 3D micro-physiological systems for DILI testing in drug discovery and development

抄録

While animals produce high wrong predictions of drug-induced liver injury (DILI) to man, human micro-physiological systems (MPS) raised high expectations that their use in industrial practice could improve the hepatoxicity prediction. Among the available MPS, human 3D primary hepatic spheroids are most promising in terms of their liver-like features, scalability, data quality, reproducibility, and miniaturization which make them compatible for standardized industrial high-throughput applications. Moreover, human 3D hepatic spheroids predict hepatotoxicity more accurately than primary human hepatocyte cultures (Proctor et al., Archives of toxicology vol. 91,8 (2017): 2849-2863). In the current study human 3D hepatic spheroids were further evaluated by a large data set of clinically applied drugs which were selected from the FDA DILIrank dataset. In the current study the cytotoxicity of 82 drugs were investigated by their ATP content after 7-day treatment. The cellular ATP IC50 values were put in relation to the clinical exposures (total plasma Cmax). The cytotoxicity of the FDA classified drugs correlated well with the in vivo hepatotoxicity. Hepatotoxic drugs had lower cellular ATP IC50 to total plasma Cmax ratio (Ra/c) than non toxic drugs. At an empirical Ra/c score below 90 drugs were flagged as hepatotoxic. 80.6% of “Most-DILI-Concern” drugs were correctly predicted as hepatotoxic, whereas 84.2% of “No-DILI-Concern” drugs were correctly predicted as safe. A similar positive correlation was obtained for the severity class and label section of the drugs tested, with the most hepatotoxic drugs having lower Ra/c scores than less hepatotoxic drugs. In conclusion, the results demonstrate that human 3D hepatic spheroids is predictive and pragmatic MPS that can be applied in drug development at the industrial setting.