Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

Abstract

Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans. Conversely, compounds associated with the occurrence of DILI in phase 3 studies or after market release are often tested negative in regulatory toxicology studies. Idiosyncratic DILI is a rare event that is precipitated in an individual by the simultaneous occurrence of several critical factors. These factors may relate to the host (e.g. human leukocyte antigen polymorphism, inflammation), the drug (e.g. reactive metabolites) or the environment (e.g. diet/microbiota). This type of toxicity therefore cannot be detected in conventional animal toxicology studies. Several animal models have recently been proposed for the identification of drugs with the potential to cause idiosyncratic DILI: rats treated with lipopolysaccharide, Sod2^+/- mice, panels of inbred mouse strains or chimeric mice with humanized livers. These models are not suitable for use in the prospective screening of new drug candidates. Humans therefore constitute the best model for predicting and assessing idiopathic DILI.

Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent

“…APAP (mice) and ibuprofen (dogs)) (39). With specific regard to DILI, the presence of toxicity in animal models does not typically halt the progression of drug candidates into clinical development unless clear dose-dependent indicators are seen (181), due to the fact that preclinical prediction of clinical hepatotoxicity is notoriously poor (182,183). This may stem from the apparent and significant inter-species variation in xenobiotic metabolism (184), explained by differences in the structure, substrate affinities, catalytic activities, and induction of DMEs (185,186).…”

A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies

“…Regardless, rodent models which are commonly used as one of the animals'models have predictive rates of less than 40% for human DILI and resulted in second highest discontinuation rates for several drugs ( Olson et al, 2000 ). In “ Preventing drug-induced liver injury : how useful are animal models ?” Ballet argues that no animal models are useful for predicting the most common forms of human DILI at all and that humans themselves are best models for DILI ( Ballet, 2015 ). Indeed, no good pre-clinical model of DILI in which human concentration-time profiles of pharmaceuticals are examined exists as of yet.…”

Characterization of hepatocyte-based in vitro systems for reliable toxicity testing

“…This is specifically valid for idiosyncratic types of drug-induced liver injury, which are difficult to study in vitro. In addition, non-hepatic factors, like the gut microbiota or the presence of pro-inflammatory factors, have been identified in the last few years as major determinants in the manifestation of chemical-induced liver toxicity (Ballet 2015). Such factors should be included in future liver-based in vitro systems and are anticipated to influence hepatocyte functionality and toxicity responses.…”