Evolving IVIVE: Analysis of human & animal Liver MPS for improved understanding of species-specific DILI 

The leading cause of compound attrition during therapeutics development is drug-induced liver injury (DILI). It is well known that animal models, whilst useful in understanding systemic toxicity, are inherently different to humans and therefore do not always predict human DILI effectively.

The advent of organ-on-a-chip (OOC) or microphysiological systems (MPS) now provides drug developers with an improved method to predict human outcomes, however direct in vivo data comparisons are required to further prove their translatability.

To bridge this gap, the PhysioMimix^® platform was used to culture primary human, beagle dog or Sprague Dawley rat hepatocytes in 3D microtissues under perfusion in the Liver-12 plate for 8-14 days. The resulting tissues were assessed for their ability to predict in vivo responses using a panel of 8 compounds using functional and clinical readouts including albumin, urea, LDH and ALT.

The DILI assay successfully predicted species specific toxicity, where compounds such as sitaxentan (DILI Rank 8) demonstrated clear hepatotoxicity in the human MPS but not in animal MPS. Tolcapone induced hepatotoxicity across the models, whilst entacapone showed no hepatoxicity in the animals. However, the human MPS predicted hepatoxicity at higher concentrations of entacapone in clinical markers (ALT, albumin), demonstrating its sensitivity to predict rarer cases of DILI.

Together, these data demonstrate the ability of MPS to provide accurate IVIVE translatability and therefore its importance as a drug development tool to understanding species-specific toxicity and improve transition of therapeutics to the clinic.