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- W3004855861 abstract "The FDA's global Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is designed to remove an over-reliance on hERG data to predict human clinical cardiac risk. Recent results suggest that inclusion of additional cardiac ion channels and assays (e.g. peak and late Nav1.5, Cav1.2, dynamic hERG) improves the accuracy of risk prediction in in silico cardiacaction potential models. CiPA working groups currently use a mixture of manual and automated patch clamp (APC) platform data, but future CiPA drug screening will likely rely on APC data. We set out to determine if APC cardiac ion channel data could be used in current in silico models to reliably predict clinical proarrhythmic risk. All data was generated on the gigaseal QPatch 48 system (Sophion, Denmark). In vitro cardiac assays, including ΔKPQ, late Nav1.5 and dynamic hERG kinetic assays (Milnes et al., 2010), used CiPA step-ramp and industry standard voltage protocols. IC50 potencies for compounds from each CiPA risk category were applied to the official FDA optimised dynamic O’Hara-Rudy (ORd) model (Dutta et al., 2017), with qNet scores being generated. We show that high quality APC data from CiPA cardiac assays can effectively predict proarrhythmic risk of some, but not all, drugs in FDA in silico models. However, two areas need improvement: 1. Compounds exhibiting slow binding on-rates underperform in certain assays, including our current dynamic hERG assay. 2. The potency of CiPA compounds, such as verapamil, against Cav1.2 is influenced by the voltage protocol used and the state- and frequency-dependence of Cav1.2 channel activation. It is critical that optimised, rather than standardised, assay protocols are used to reduce such variability and improve the accuracy of cardiac risk prediction with APC data." @default.
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- W3004855861 date "2020-02-01" @default.
- W3004855861 modified "2023-10-18" @default.
- W3004855861 title "Using New In vitro Cardiac Ion Channel Assays and In Silico Models to Predict Proarrhythmic Risk with Automated Patch Clamp Data" @default.
- W3004855861 doi "https://doi.org/10.1016/j.bpj.2019.11.3201" @default.
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