Chapter 6: Current Developments in the Use of Human Stem Cell Derived Cardiomyocytes to Examine Drug-induced Cardiotoxicity
Published:09 Aug 2016
Cardiac toxicity is a major concern in drug development, and it is imperative that clinical candidates are thoroughly tested for adverse effects earlier in the drug discovery process. Cardiac toxicity arrhythmia has become the single most common cause of the withdrawal or restrictions of previously marketed drugs. The recent advances in stem cell technology and particularly in differentiating embryonic or induced-pluripotent stems cells have created a unique opportunity for providing physiologically relevant and disease relevant model systems for preclinical safety assessment of compounds. Current studies have shown that in vitro tests utilizing human stem cell-derived cardiomyocytes might be beneficial for preclinical risk evaluation. The Comprehensive In Vitro Proarrhythmia Assay (CiPA), which is a joint initiative of various organizations including the U.S. FDA and the EMA, also includes stem cell cardiomyocyte for cardiotoxicity testing. The anticipated final outcome from CiPA is that it will modify existing ICH (International Conference on Harmonisation) S7A/B guidelines for nonclinical safety pharmacology testing of pharmaceuticals, and will eliminate ICH E14 guidelines, which warrants Thorough-QT (TQT) study in humans. Assays based on human stem cell-derived cardiomyocytes could complement or potentially replace cardiac toxicity tests currently used for lead optimization and further development of new drugs. However, such a development could only occur after further validation.