Comparison of Cardiac Action Potential between Human Pluripotent Stem Cell-Derived Cardiomyocytes(hPSC-CM) and CiPA (Comprehensive in vitro proarrhythmic assay)-based In Silico Simulation
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For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG blocks, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of excluding drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. The CiPA project consists of four components: in vitro multiple cardiac ion channel evaluation, in silico computer simulation, cardiotoxicity evaluation using human stem cell-derived cardiomyocytes, and ECG evaluation. Here, we compared cardiac action potential using positive (Isoproterenol), negative (Diltiazem), false positive (Astemizole), and false negative (Levofloxacin) drugs between in silico computer simulation and human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CM). To distinguish between positive and negative, cardiotoxicity was determined by considering whether the action potential duration at 90% repolarization (APD90) changed by more than 10% and the Cmax of the drug. We observed that drug-induced action potential shape changes were similar between in vitro clamp studies and in silico simulations.
Abstract
For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG blocks, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of excluding drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. The CiPA project consists of four components: in vitro multiple cardiac ion channel evaluation, in silico computer simulation, cardiotoxicity evaluation using human stem cell-derived cardiomyocytes, and ECG evaluation. Here, we compared cardiac action potential using positive (Isoproterenol), negative (Diltiazem), false positive (Astemizole), and false negative (Levofloxacin) drugs between in silico computer simulation and human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CM). To distinguish between positive and negative, cardiotoxicity was determined by considering whether the action potential duration at 90% repolarization (APD90) changed by more than 10% and the Cmax of the drug. We observed that drug-induced action potential shape changes were similar between in vitro clamp studies and in silico simulations.
참고문헌 (10)
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