Abstract
The CiPA initiative recommends the combined use of in vitro experiments with Modeling and Simulation techniques to early assess a drug-induced proarrhythmic risk. QT/TdP Risk Screen is a cloud-based tool that uses Machine Learning to classify a compound as clinically safe or unsafe at the concentration of interest in line with the CredibleMeds classification criteria.
Using QT/TdP Risk Screen, the cardiac safety of Moxifloxacin, Quinidine, Ranolazine, Verapamil, Chloroquine, and Hydroxychloroquine was assessed. In vitro IC50 and Hill coefficients for hERG and INaL were obtained with the CiPA voltage protocol, while for IKs and ICaL they were assessed following Okada et al., 2015. All channels were assayed at room temperature. The hERG channel for Chloroquine and Hydroxychloroquine was assayed also at physiological temperature. The IC50s and Hill coefficients and the concentration of interest were used as input to run QT/TdP Risk Screen. The tool provided in output for each compound at each concentration the torsadogenic indices and the associated clinical risk.
QT/TdP Risk Screen well classified Moxifloxacin, Quinidine, Chloroquine and Hydroxychloroquine as unsafe, in agreement with the clinical classification of CredibleMeds. The torsadogenic indices of Chloroquine and Hydroxychloroquine reflected the temperature¿s effect on the hERG IC50 and Hill coefficients assessment in line with expectations. QT/TdP Risk Screen classified Ranolazine and Verapamil as unsafe, whereas their clinical label is Conditional Risk of TdP and Not Classified, respectively. Ranolazine misclassification may be related to the tool¿s underrepresentation of the interaction between the hERG and NaL channels. Verapamil misclassification could be attributed to several reasons like a single pore model might not capture all Verapamil effects on the cardiac cell and/or the electrophysiological model does not adequately estimate the ability of ICaL to counteract IKr. In addition, some authors claim that the Verapamil¿s IKr block tends to be overestimated when assessed with voltage clamp experiments.
This use case showed how QT/TdP Risk Screen can reliably predict clinical risk of Torsade de Points in early preclinical development when complemented by in vitro experiments. The tool is available on the secure and user-friendly InSilicoTrials.com platform.
