According to the pioneers of the human-on-a-chip in vitro system, they announced the use of its unique multi-organ model to successfully measure the concentration and metabolism of two known cardiotoxic small molecules over time, to accurately describe the drug behavior and toxic effects in vivo. Furthermore, the findings support the potential of body-on-a-chip systems to transform the drug discovery process.
In collaboration with AstraZeneca and in a study published in Nature Scientific Reports, Hesperos described how the researchers used a pumpless heart model and a heart, liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine, an antihistamine that was banned due to toxic cardiac effects, as well as determine its mechanism of toxicity.
As discovered by the research, there was a time-dependent, drug-induced response in the heart model. They conducted additional experiments by adding a metabolically competent liver module to the Hesperus Human-on-a-chip® system to observe what happened when terfenadine was converted to fexofenadine. Doing this process, the team was able to determine the driver of the pharmacodynamic (PD) effect and develop a mathematical model to predict the impact of terfenadine in preclinical species. This situation 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 outcomes in the future.
President and CEO, Hesperos, Inc and Profesor Emeritus, Cornell University, Dr. Shuler said that the ability to examine PKPD relationships in vitro would enable scientists to understand compound behavior before in vivo testing, providing high cost and time savings. Dr. Shuler explained further that they are excited about the potential of this technology to help them ensure that potential new candidates have a higher probability of success during the clinical trial process.
One of the primary measurements the researchers used to assess the electrical properties of the heart is the QT interval, which approximates the time taken from when the cardiac ventricles start to contract to when they finish relaxing. Prolongation of the QT interval on the electrocardiogram can lead to a fatal arrhythmia known as Torsade de Pointes. As a result, it is a mandatory requirement before the first-in-human administration of potentially new drug candidates that their ability to inhibit the hERG channel (a biomarker for QT prolongation) is investigated.
Hesperos, Inc. is the first company spun out from the Tissue Chip Program at NCATS (National Center for Advancing Translation Sciences), which was established in 2011 to address the long timelines, steep costs, and high failure rates associated with the drug development process. As at present, Hesperos gets its fund through NCATS' Small Business Innovation Research program to undertake these studies and make tissue chips technology available as a service-based company.
