Xenobiotic-induced cardiotoxicity is a major concern for both pharmaceuticals and chemicals in the marketplace. For drugs, "Thorough QT/corrected QT (QTc)" (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. For other chemicals, cardiotoxicity is not routinely assessed, and is largely inferred from epidemiologic data. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a diverse sample of human subjects can serve as a "TQT study in a dish," improving cardiotoxicity assessments for both pharmaceutically and chemicals in commerce. For 10 positive and 3 negative control drugs, in vitro concentration-QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration-QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10 ms QTc prolongation would be breached were also consistent with in vivo evidence. This "TQT study in a dish," consisting of a population-based iPSC-derived cardiomyocyte model and Bayesian concentration-QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern. These results demonstrate the potential for replacing a multi-million dollar clinical trial – the Thorough QT/QTc study – with an in vitro-in silico model. Moreover, because cardiotoxicity clinical trials are not performed for non-pharmaceuticals, such a model could fill a critical gap in chemical toxicity testing.
1. Describe current practices in cardiotoxicity assessment for xenobiotics.
2. Explain how induced pluripotent stem cell-derived cardiomyocytes may be useful in advancing cardiotoxicity assessment.
Research And Development
Medical Laboratory Technician13%
Clinical Laboratory Scientist2%