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Dishing Out the QT Risk

Author: Sarah M. Robertson, PharmD on September 16, 2019

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Early identification of QT-prolongation or pro-arrhythmic risk for drugs in development has historically relied on binding or functional assays for hERG and other ion channels, with follow-up studies in animals. This hERG-to-animal approach entails a jump from simple and relatively uncertain to costly and complex, whereas a cellular system that captures the complexity of human ion channels might be a better alternative to de-risk clinical development.

Enter the dish. Utilization of induced pruripotent stem cell-derived cardiomyoctes (iPSC-CMs) for prediction of drug-induced arrhythmias is a hot topic, with the approach recognized and supported by the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative (https://cipaproject.org). Despite the enthusiasm for this approach, many questions remain.  

A recently published study in Clinical Translational Science (CTS) adds to our growing knowledge around the usefulness of iPSC-CMs in making clinical QT prolongation predictions (Clinical Trial in a Dish: Personalized Stem Cell-Derived Cardiomyocyte Assay Compared with Clinical Trial Results for Two QT-Prolonging Drugs). Blinova and colleagues measured the action potential response of two QT-prolonging drugs in vitro using subject-specific iPSC-CMs. These in vitro data were compared to individual subject QT effects from a clinical study conducted with the same drugs, in order to determine the correlation of individual responses in vitro and in clinic. A lack of correlation was observed for both drugs, leading the authors to some interesting hypotheses regarding the limitation of iPSCs and to opine on the importance of standardization and opportunities for future studies. Consistent with the CTS mission of allowing “negative” results to speak as loud as positive results, the lack of correlation reported in this publication speaks volumes.

 

Image by Blinova. et al. Clin. Trans. Sci., https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12674, is licensed under CC BY-NC 4.0. ©2019 The Authors.

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