In vitro BA-LRA can help detect small molecule drugs for drug-induced liver injury

Reviewed by Emily Henderson, B.Sc.Oct 13 2020

BioIVT, a leading provider of research models and services for drug and diagnostic development, today announced the publication of research describing the use of HEPATOPAC^® cultures with a targeted in vitro assay to identify small molecule drugs with high potential for drug-induced liver injury (DILI).

DILI contributes to the high failure rate of drug candidates in clinical development; but frequently DILI risk is not evident until late in clinical trials. There remains a need for better preclinical models to screen drug candidates for DILI risk during the lead selection and optimization process.

The in vitro Bioactivation Liver Response Assay (BA-LRA) is a method based on a set of liver gene expression biomarkers that respond quantitatively to chemically reactive metabolites that are predicted to trigger bioactivation-mediated clinical DILI.

BioIVT's HEPATOPAC model was selected for the in vitro BA-LRA because of its long-term viability and demonstrated in-vivo relevance. The HEPATOPAC model is an in vitro bioengineered co-culture of primary hepatocytes and fibroblasts, which is used extensively for liver-based safety, metabolism, and efficacy evaluations of small molecule drug candidates.

The work, conducted by scientists at Merck Research Laboratories and published in the peer reviewed journal Toxicological Sciences, describes application of the in vitro BA-LRA using the HEPATOPAC model to evaluate 93 compounds known to be DILI positive or negative in humans.

The assay was able to differentiate the drugs with lower DILI risk with an 81% sensitivity and 90% specificity in the rat HEPATOPAC model and a 68% sensitivity and 86% specificity in the human HEPATOPAC model.

The high in-vitro in-vivo correlation of HEPATOPAC cultures, combined with their long-term viability makes this an excellent system for novel ADME Tox and disease models. This publication adds to the body of evidence for the utility of these assays as early de-risking tools to reduce the risk of drug induced liver injury in pharmaceutical development."

Dr. Christopher Black, Senior VP ADME, BioIVT