%0 Journal Article %1 Abi-Gerges2017 %A Abi-Gerges, Najah %A Pointon, Amy %A Oldman, Karen L. %A Brown, Martin R. %A Pilling, Mark A. %A Sefton, Clare E. %A Garside, Helen %A Pollard, Christopher E. %D 2017 %J Journal of Pharmacological and Toxicological Methods %K Ca2 +_transient Cardiac_safety Drug_discovery_and_development Extracellular_field_potential Human_stem_cell-derived_cardiomyocytes Pro-arrhythmia QT_prolongation %R 10.1016/j.vascn.2016.09.001 %T Assessment of extracellular field potential and Ca 2 + transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes %X 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 Ca 2 + 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 Ca 2 + 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.

@article{Abi-Gerges2017, abstract = {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{\textregistered} 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 Ca 2 + transient FLIPR{\textregistered} 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 Ca 2 + transient data, the values were 67{\%}/100{\%} and 78{\%}/53{\%} at EFTPC and TTC, respectively. Thus, iCell{\textregistered} 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.}, added-at = {2019-06-17T23:34:05.000+0200}, author = {Abi-Gerges, Najah and Pointon, Amy and Oldman, Karen L. and Brown, Martin R. and Pilling, Mark A. and Sefton, Clare E. and Garside, Helen and Pollard, Christopher E.}, biburl = {https://www.bibsonomy.org/bibtex/2a277fe44d6242ff1e79a61fd1ffca110/fcdi}, doi = {10.1016/j.vascn.2016.09.001}, interhash = {97f4a1cd74d169962ea3395c25eba085}, intrahash = {a277fe44d6242ff1e79a61fd1ffca110}, issn = {1873488X}, journal = {Journal of Pharmacological and Toxicological Methods}, keywords = {Ca2 +_transient Cardiac_safety Drug_discovery_and_development Extracellular_field_potential Human_stem_cell-derived_cardiomyocytes Pro-arrhythmia QT_prolongation}, timestamp = {2019-06-18T22:58:44.000+0200}, title = {{Assessment of extracellular field potential and Ca 2 + transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes}}, year = 2017 }