Assessment of extracellular field potential and Ca2+transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes.
Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free microelectrode array (parameters measured were beating period (BP), field potential duration (FPD), fast Na+amplitude and slope) and live cell, fast kinetic fluorescent Ca2+transient FLIPR® Tetra (parameters measured were peak count, width, amplitude) systems. Many FPD-altering drugs also altered BP. Correction for BP, using a Log-Log (LL) model, was required to appropriately interpret direct drug effects on FPD. In comparison with human QT effects and when drug activity was to be predicted at top test concentration (TTC), LL-corrected FPD and peak count had poor assay sensitivity and specificity values: 13%/64% and 65%/11%, respectively. If effective free therapeutic plasma concentration (EFTPC) was used instead of TTC, the values were 0%/100% and 6%/100%, respectively. When compared to LL-corrected FPD and peak count, predictive values of uncorrected FPD, BP, width and amplitude were not much different. If pro-arrhythmic risk was to be predicted using Ca2+transient data, the values were 67%/100% and 78%/53% at EFTPC and TTC, respectively. Thus, iCell® cardiomyocytes have limited value as an integrated QT/TdP assay, highlighting the urgent need for improved experimental alternatives that may offer an accurate integrated cardiomyocyte safety model for supporting the development of new drugs without QT/TdP effects.
Safety and ADME Translational Sciences, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK. Electronic address: najah.abigeorges@hotmail.com.
Najah
N
Abi-Gerges
Safety and ADME Translational Sciences, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
Amy
A
Pointon
Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0FZ, UK.
Karen L
KL
Oldman
Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0FZ, UK.
Martin R
MR
Brown
Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0FZ, UK.
Mark A
MA
Pilling
Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0FZ, UK.
Clare E
CE
Sefton
Discovery Safety, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
Helen
H
Garside
Safety and ADME Translational Sciences, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
Christopher E
CE
Pollard
D000200:Action Potentials / Q000187:drug effects*; D015220:Calcium Channels / Q000378:metabolism*; D066126:Cardiotoxicity; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage
D015220:Calcium Channels; D003470:Culture Media; D004364:Pharmaceutical Preparations
Ca(2+) transient; Cardiac safety; Drug discovery and development; Extracellular field potential; Human stem cell-derived cardiomyocytes; Pro-arrhythmia; QT prolongation