About the detection of hepatotoxic compounds
Background and Purpose: The development of therapeutic drugs is often hampered by hepatotoxicity. Detecting possible hepatotoxic compounds as early as possible during the development process helps to channel resources to therapeutic compounds. However, the current safety assessment still regularly fails to predict hepatotoxicity in humans, leading to numerous drugs being stopped in the late stage of development. Micro-physiological systems are in vitro systems focusing on the accurate modeling of physiological organ features, intending to have better predictive power than less physiological systems.
Human liver microtissues, comprising spherical co-cultures of primary parenchymal and non-parenchymal liver cells, recapitulate essential liver features and have demonstrated better hepatotoxicity prediction accuracy compared to planar hepatocyte cultures. This study evaluates the predictive power of 3D liver microtissues by benchmarking the cytotoxicity (cellular ATP IC50) of a large drug set of FDA-approved drugs, screened in human liver microtissues, against the in vivo drug-induced liver injury (DILI) annotation and drug label information of hepatotoxicity.
Methods: A large drug set of 152 FDA-approved small molecular drugs with balanced clinical hepatotoxicity and a broad representation of drug classes were screened in human liver microtissues for hepatotoxicity assessment. The relevance of the liver microtissue for hepatotoxicity assessment was evaluated by comparing the cytotoxicity (cellular ATP IC50) of the liver microtissues with the in vivo hepatotoxicity and total peak plasma concentration reported from the clinics.
Results: The cytotoxicity of the drugs correlated well with all three types of classification, "DILI concern class,” “Liver injury description,” and “Hepatotoxicity related warning,” reported in the FDA resource, the DILIrank dataset. This study disclosed that 86% of withdrawn drugs and 78% of drugs leading to fatal hepatotoxicity were accurately predicted as hepatotoxic, whereas 85.3% of the non-toxic drugs were accurately predicted as such. The correlation between the in vitro cytotoxicity and the hepatotoxicity of the tested drugs demonstrates the utility of human liver microtissues for the detection of hepatotoxic compounds early in the drug development process.
Conclusions: The correlation between the in vitro cytotoxicity and the hepatotoxicity of the tested drugs shows the value of human liver microtissues for the detection of hepatotoxic compounds early in the drug development process.
Download the poster about the early detection of hepatotoxic compounds
