A new organ-on-a-chip system can predict human toxicity that was undetected in animal studies for drugs halted in clinical trials and emphasizes species-specific responses in liver toxicity.

HUMAN HEALTH ISSUE

Rats, dogs and other animals are used to test whether drugs are toxic to humans before the drugs are given to people. Candidate drug testing using standard preclinical animal models cannot accurately predict which compounds are likely to cause drug-induced liver injury in humans. A previous study found that the animal tests correctly identified only 71 percent of drug toxicities. It is not uncommon for compounds to be discontinued due to liver toxicity observed in rats or dogs prior to testing in humans because of uncertainties on the human relevance of these findings. And for those compounds that end up on the market, drug-induced liver injury is the most common reason cited for withdrawal of an approved drug.

ANIMAL FREE SCIENCE INNOVATION POTENTIAL

A lab grown liver-on-a-chip based on human liver cells, which mimics a real human liver, may be a better predictor of drug toxicity or safety than standard animal models. Scientists at Emulate have developed a liver-on-a-chip consisting of either rat, dog, or human hepatocytes, endothelial cells, Kupffer cells, and stellate cells. Using these microfluidic chips, they confirmed several cases of species-specific toxicity.

In a 1993 clinical study with the compound Fialuridine, unexpected toxicity led to the death of 5 out of 15 patients from liver failure, two further participants required liver transplantation. This toxicity was unusual in that it was not predicted by animal studies. The scientists from Emulate were able to confirm human-specific toxicity by Fialuridine in the human liver-on-a-chip, while at the same time demonstrating the lack of toxicity in the companion animal liver-chips.

They also tested a compound that was deemed unsafe and removed from clinical trials in humans. Their experimental findings confirmed that the compound induced fibrosis in a rat liver-chip but did not alter hepatocyte function in human chips. The question then immediately comes to mind whether this compound could have proven safe and beneficial in humans.

Together these results are a proof of concept that an in-vitro human model can be a better predictor of human toxicity and safety than in-vivo animal models and that the continued use of the animal model in pre-clinical drug testing poses both a danger to human health and a hindrance to medicinal development.

SCIENTIFIC ABSTRACT

Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.

Source: K.-J. Jang et al. Reproducing human and cross-species drug toxicities using liver-chips. Science Translational Medicine. Vol. 11, November 6, 2019. doi.org/10.1126/scitranslmed.aax5516.