Archived Webinar

Thorough QT-QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration-QTc Relationships

Presenter: Weihsueh A. Chiu, PhD, Texas A&M University

Presenter: Weihsueh A. Chiu, PhD, Texas A&M University 

The “Thorough QT/QTc” (TQT) study is a cornerstone of clinical cardiovascular safety assessment for pharmaceuticals, designed to assess whether QTc is prolonged by no more than 10 msec at 95% confidence. We hypothesized that the concentration-QTc (C-QTc) modeling of iPSC-derived cardiomyocytes from a diverse sample of human subjects can serve as a “TQT study in a dish,” providing accurate prediction of the range of concentrations that would be below the regulatory threshold. 

Methods: Using a population of iPSC-derived cardiomyocytes derived from 27 donors without reported cardiovascular disease, we tested 10 positive and 3 negative control drugs with known in vivo C-QTc relationships based on pharmacokinetic-pharmacodynamic modeling. We used Ca2+ flux imaging to measure in vitro beating, identifying the peak decay-rise ratio as an in vitro surrogate for in vivo QTc. We fit the C-QTc relationship using a population Bayesian model, and compared posterior predictions to in vivo C-QTc reported in the literature. Finally, we demonstrated clinical translation by predicting the percent confidence that the regulatory threshold of 10 msec QTc prolongation would be breached. 

Results: The in vivo C-QTc relationships were accurately predicted for all 13 drugs. Population-based predictions were more accurate than predictions based single-donor cardiomyocytes. Nine of 10 positive controls and 2 of 3 negative controls were definitively identified as being above and below, respectively, the regulatory threshold for QTc prolongation. 

Conclusions: A “TQT study in a dish” is feasible using a population-based iPSC-derived cardiomyocyte model combined with population Bayesian C-QTc modeling, and provides an accurate prediction of the in vivo concentration range below the threshold of regulatory concern. This approach has broad regulatory science implications for both pharmaceutical testing as well as environmental toxicants.