Lab models that mimic the human heart and liver systems were able to correctly predict the toxicity of two test drugs in a study, reinforcing their potential as drug discovery tools.
The ‘human-on-a-chip’ devices – one modelling the heart and the other the liver – were used in tandem to measure the concentration and metabolism of two known small-molecule drugs that can damage the heart, and provided an accurate readout of their behaviour and toxic effects in the body.
Hesperos says this is “the first time an in vitro human-on-a-chip system has been shown to predict in vivo outcomes, which could be used to predict clinical trial outcomes in the future.”
The research – published in Nature Scientific Reports – add to the body of research suggesting that “microphysiological models could have a transformative effect on drug discovery”, according to the authors.
The heart:liver chips, manufactured by US biotech Hesperos, were put through their paces using the antihistamine terfenadine and a failed AstraZeneca small-molecule drug, both known be cardiotoxic.
In the case of a terfenadine – which was eventually banned because of its effects on the heart – the in vitro system was able to show the direct toxicity of the drug in the heart module, as well as model the effect of metabolising the drug to fexofenadine with the addition of the liver module. The tests teased out the pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine over time and the mechanism of toxicity.
Meanwhile, for the AZ drug, the scientists were able to correctly determine the cardiotoxic response to its metabolite using the heart:liver system. The toxicity of the metabolite wasn’t discovered until fairly late on in the preclinical development of the drug, so using Hesperos’ system could have caused the programme to fail faster and avoided unnecessary cost and effort.
“The ability to examine PKPD relationships in vitro would enable us to understand compound behaviour prior to in vivo testing, offering significant cost and time savings,” said Dr Michael Shuler, chief executive of Hesperos and professor emeritus at Cornell University.
“We are excited about the potential of this technology to help us ensure that potential new drug candidates have a higher probability of success during the clinical trial process.”
The hope is that microphysiological systems could eventually significantly reduce the need for animal studies in drug discovery.
Earlier this year, Hesperos published data suggesting its chips were able to mimic the 28-day experiments typically used in animals to evaluate the systemic toxicity of drug and cosmetic compounds.