Prediction of human toxicity early in the drug development process remains a major challenge. Given the high attrition rates in preclinical drug discovery due to hepatotoxicity and the multifactorial, complex nature of idiosyncratic drug-induced liver injury (DILI), no single system has yet emerged as a universal preclinical testing platform. Although  human in vitro models are becoming increasingy important in DILI research, the development of more physiologically relevant liver models and careful selection of control DILI positive and DILI negative drugs are requisites to better predict DILI liability of new drug candidates. A recent study published in the  Journal of Hepatology by a panel of international experts from the ProEuroDILI Network COST Action, led by Isabel Lucena (Hospital Universitario Virgen de la Victoria, Málaga) y Jose C. Fernandez-Checa (IIBB-CSIC), describes a thematic output focusing on all aspects of DILI (clinical, basic, toxicology  and translational hepatology) in the pre-clinical drug development process. From an initial review of nearly 3,000 literature-based studies using hepatotoxicity assays, only 51 met the rigorous inclusion criteria as bona fide control compounds.

The selection of the positive and negative control compounds described in this systematic study arises as a critical tool in pre-clinical drug discovery industry to validate assays, establish reference points, and provide context for assessing the hepatotoxicity and safety profiles of new drug candidates. This thematic output is of paramount importance to all players involved in the drug development process, offering a standardized approach to assess hepatotoxic risks. These findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approah to drug safety assessment.

 

Reference of the study:

Segovia-Zafra A., Villanueva-Paz M., Serras A.S., Matilla-Cabello G, Bodoque-García A, Di Zeo-Sánchez D, Niu H, Álvarez-Álvarez I, Sanz-Villanueva L, Godec S, Milisav I, Bagnaninchi P, Andrade RJ, Lucena MI*, Fernández-Checa JC*, Cubero FJ, Miranda JP, Nelson LJ.

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network. Journal of Hepatology 2024 May 2:S0168-8278(24)00325-8.doi: 10.1016/j.jhep.2024.04.026

* Corresponding authors