Keywords
Cardiotoxicity; hSC-CMs; Proarrhythmic; Potassium channel; Repolarization
Abstract
The average cost to develop and gain marketing approval for a new drug is estimated to be $2.558 billion according to the most recent analysis by the Tufts Center for the Study of Drug Development. Among solutions to rein in the rising development costs, early and efficient assessment of a drug’s cardiotoxicity is essential to reduce drug attrition in late phases of development or drug withdrawal after approval. This article aims to provide a basic understanding of different types of cardiotoxicity followed by an overview of current and new methodologies in cardiotoxicity testing. Emphasis is placed on emerging technologies for the evaluation of proarrhythmia which include the use of human stem cell derived cardiomyocytes and in silico modeling. These developments represent an evolving paradigm shift which laid the foundation for the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay), a global effort to establish a mechanistically based new system for cardiac safety testing. This is a shift from the current approach which relies on over simplified in vitro assays that measure blockade of a single heterologously expressed potassium ion channel (the Kv 11.1 or hERG channel). Although increasing levels of complexity of the new system pose new challenges, substantial progress has been made and regulatory implementation is not far away.
Citation
Sun W. Cardiotoxicity Testing in Drug Development. SM J Cardiolog and Cardiovasc Disord. 2016; 2(2): 1007s4.