Predicting in-vivo results

Hesperos’ heart-liver Human-on-a-Chip correctly determines cardiotoxic mechanisms preclinically

Mel J. Yeates
ORLANDO, Fla.—In June, Hesperos Inc., a pioneer of “human-on-a-chip” in-vitro techology, announced the use of its multi-organ model to successfully measure the concentration and metabolism of two known cardiotoxic small molecules over time, and to accurately describe the drug behavior and toxic effects in vivo. The findings further support the potential of body-on-a-chip systems to transform the drug discovery process.
“There are about four or five other companies who are able to do these human-on-a-chip models,” Dr. James Hickman, chief scientist at Hesperos and a professor at the University of Central Florida, tells DDNews. “One of the things that differentiates our model is its use of a serum-free medium. Most research of this type uses calf serum, drained from a baby cow who is either dying or terrified, so it is full of hormones that are not really good for cells. The cells de-differentiate, which can create problems for the researchers. By using a serum-free medium, we’ve been able to figure out how to keep four to five cell types alive for up to 28 days—an important number because it’s the time required for systemic toxicity experiments in animals.”
“Another differentiator is our pumping mechanism,” Hickman adds. “Instead of using a compressive type pump, we just simply use gravity. We believe this is actually better for the cells, as it causes less stress.”
In an article published in Nature Scientific Reports in collaboration with AstraZeneca, Hesperos describes using a pumpless heart model and a heart/liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PK/PD) relationship for terfenadine, as well as to determine its mechanism of toxicity.
The study found there was a time-dependent, drug-induced response in the heart model. Researchers then added a metabolically competent liver module to observe what happened when terfenadine was converted to fexofenadine. The scientists were able to determine the driver of the pharmacodynamic effect and develop a mathematical model to predict the effect of terfenadine in preclinical species.
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.
Understanding the inter-relationship between PK/PD is crucial in drug discovery and development. The maximum drug effect isn’t always driven by peak drug concentration. In some cases, time is a critical factor, but often this concentration-effect-time relationship only comes to light during the advanced stages of the preclinical program, and the data cannot be reliably extrapolated to humans.
“It is costly and time-consuming to discover that potential drug candidates may have poor therapeutic qualities preventing their onward progression,” Hickman notes. “Being able to define this during early drug discovery will be a valuable contribution to the optimization of potential new drug candidates.”
One of the main measurements used to assess the electrical properties of the heart is the QT interval. Prolongation of the QT interval can lead to a fatal arrhythmia known as Torsades de Pointes.
“We specifically looked at FPD (QT) elongation, because safety considerations over cardiac arrhythmia are one of the major contributors to drug removal during clinical trials and also for future black box warnings of approved drugs. The ability to predict human QT complications in the preclinical stage will help lessen the number of black box warnings, drugs that fail during clinical trials, and endangerment to human lives,” says Dr. Michael L. Shuler, president and CEO of Hesperos and professor emeritus, Cornell University.
“Terfenadine was specifically chosen [because it] has been used extensively as a control parent compound for QT elongation studies and investigation for Torsades de pointes,” he continues. “Interestingly, terfenadine was removed from the market because of QT concerns and was one of the reasons the FDA enacted more stringent guidelines on testing cardiac effects of all potential therapeutics.”
In order to test the viability of their system in a real-world drug discovery setting, the Hesperos team collaborated with scientists at AstraZeneca to test terfenadine. The molecule was assessed for hERG inhibition early on, and it was concluded to have a low potential to cause in-vivo QT prolongation up to 100 μM. In later preclinical testing, the QT interval increased by 22 percent at a concentration of just 3 μM. Subsequent investigations found that a major metabolite was responsible. Hesperos was able to detect a clear PD effect at concentrations above 3 μM, and worked to determine the mechanism of toxicity of the molecule.
The ability of these systems to assess cardiac function non-invasively in the presence of both parent molecule and metabolite over time, using multiplexed and repeat drug dosing regimes, provides an opportunity to run long-term studies for chronic administration of drugs to study their potential toxic effects.
“Ideally, the incorporation of human-on-a-chip PK/PD models into the FDA approval process would eliminate the need for animal models. Animal models are just really poor predictors of what’s going to happen in the human,” Hickman comments. “And there are some diseases that have no animal models, and probably never will, because of the expense. Our human-on-a-chip system could be a game changer for rare diseases. We can take diseased cells and build phenotypic models to be able to reproduce aspects of the disease, then test compounds that ameliorate the effects of the disease while monitoring toxicity.
“Our models can also be used to re-examine existing or failed drugs to determine their potential efficacy in other indications. And they can help shorten drug discovery timelines and expenses significantly. By working directly with medicinal chemists and testing minuscule amounts of precious compounds, our models make it possible—and affordable—to test several formulations of promising drug candidates, rather than having the pharma companies select one and put all their eggs in that basket.”
“I expect that this will become a mainstream technology in the drug development process within the next three to five years, and that we will be able to go directly from our data into clinical trials and maybe into patients for rare diseases. The most sophisticated human-on-a-chip system would be one that can handle 28-day systemic toxicity experiments, and we’re working on that currently,” says Shuler. “The day when we can build a multi-organ system that is accepted for systemic toxicity, we believe we won’t need animals anymore. In the near future, we are looking at adapting an immune system component into our technology.”
“We really believe we can change the world for the better by creating a new paradigm for drug discovery,” Hickman concludes.
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