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In vitro chips predict in vivo results
07-04-2019
by Mel J. Yeates  |  Email the author
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ORLANDO, Fla.—Hesperos Inc., pioneers of the “human-on-a-chip” in vitro system, has 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.
 
“The ability to examine PKPD relationships in vitro would enable us to understand compound behavior prior to in vivo testing, offering significant cost and time savings,” said Michael L. Shuler, Ph.D., president and CEO of Hesperos and professor Emeritus, 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.”
 
In an article published in Nature Scientific Reports, in collaboration with AstraZeneca, Hesperos described how they used a pumpless heart model and a heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PK/PD) relationship for terfenadine, an antihistamine banned due to toxic cardiac effects, as well as to determine its mechanism of toxicity.
 
The study found there was a time-dependent, drug-induced response in the heart model. Further experiments were conducted, adding a metabolically competent liver module to the Hesperos Human-on-a-Chip system to observe what happened when terfenadine was converted to fexofenadine. The researchers were able to determine the driver of the pharmacodynamic effect and develop a mathematical model to predict the effect of terfenadine in preclinical species.
 
The study article points out that “although several groups have developed computational models to analyze data from MPS [microphysiological systems] models, no-one has yet published data on quantitative translation of MPS data to in vivo outcome, whether that be in animals or humans.” 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 pharmacokinetics and pharmacodynamics is crucial in drug discovery and development. The maximum drug effect is not always driven by the peak drug concentration. In some cases, time is a critical factor influencing drug effect, but often this concentration-effect-time relationship only comes to light during the advanced stages of the preclinical program, and often 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. Being able to define this during early drug discovery will be a valuable contribution to the optimization of potential new drug candidates,” noted James Hickman, chief scientist at Hesperos and professor at the University of Central Florida.
 
As demonstrated with terfenadine, the PKPD modeling approach was critical for understanding both the flux of compound between compartments as well as the resulting PD response in the context of dynamic exposure profiles of both parent and metabolite, as indicated by Shuler.
 
“Our simultaneous measurement of cardiomyocyte response to the cardiotoxic drug terfenadine, together with matched quantification of drug concentration in the circulating media and in the lysates of both cardiomyocytes and hepatocytes, show that the pharmacodynamic response was not driven by the concentration of drug in the media but rather by the concentration of drug within the cardiomyocytes,” states the article. “This was also supported by the lack of response of cardiomyocytes to terfenadine in the presence of metabolically competent hepatocytes and the time-dependent increase in the concentration of the hERG-inactive metabolite fexofenadine in the circulating media.”
 
“Although it is known that terfenadine binds to an intracellular site of hERG, we have for the first time in a dynamic in vitro system convincingly proven this. With this knowledge, we can determine the peak effect of terfenadine in the model, rather than at a fixed time point. This principle is fundamental to developing an understanding of drug behavior and being able to define this during early drug discovery will be a valuable contribution to the optimization of potential new drug candidates,” the article continues.
 
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 one of their failed small molecules, which was known to have a cardiovascular risk. 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% 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.
 
Hesperos is the first company spun out from the Tissue Chip Program at the National Center for Advancing Translational Sciences (NCATS), which was established in 2011 to address the long timelines, steep costs and high failure rates associated with drug development. Hesperos is currently funded through NCATS’ Small Business Innovation Research program to undertake these studies and make tissue chips technology available as a service-based company.
 
Code: E07031901

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