A web-based tool for the early identification and real time assessment of drug-induced proarrhythmic and torsade de pointes safety risk

Abstract

Abstract Introduction It is well recognized that early identification of drug-induced proarrhythmic safety risks is crucial to drug development for ethical, animal sparing and costs reduction considerations. The availability, however, of easily accessible, user-friendly tools for real time assessments of the proarrhythmic potential of chemical compounds has been lacking. The novel Tx index, implemented in the presented web-based tool, was applied to a dataset of 84 compounds. Materials and methods The tool is based on 206,766 cellular simulations of compound-induced effects on Action Potential Duration (APD) in isolated endocardial, midmyocardial, and epicardial cells and on 7,072 tissue simulations on QT prolongation in a virtual tissue. Simulations were performed by blocking the slow and the fast components of the delayed rectifier current (IKs and IKr, respectively) and the L-type calcium current (ICaL) at different levels. Based on these simulations, four Tx indices were defined as the ratio of drug concentration leading to a 10% prolongation of the APDendo, APDmid, APDepi or QT over the maximum Effective Free Therapeutic Plasma Concentration (EFTPC), respectively. A dataset of 44 non-torsadogenic and 40 torsadogenic drug compounds was used to validate the performance of the tool. The workflow of the web-based tool was built on the cloud environment, in compliance with the highest standards of security and privacy. hERG test (positive response: hERG pIC50 >6) was applied to the 84 compounds to compare performances. Results Receiver operating characteristic (ROC) curves were constructed on the four estimated Tx indices for each compound in the dataset to enable the identification of torsadogenic potential cut-off values2. These were identified as 8, 8, and 6.4 for Tx-APDendo, Tx-APDmid, Tx-APDepi and as 9.2 for Tx-QT, respectively. The classification of the 84 compounds resulted in an accuracy ranging between 87% and 88% for the four Tx indices Tx-APDendo, Tx-APDmid, Tx-APDepi and Tx-QT. Discussion and conclusion hERG block exhibits poor performance. When applying the hERG test to the 84 compounds, it exhibited a TPR of 55%, a TNR of 89%, and an A of 73%, in close agreement with previous studies. In comparison, the in silico Tx tests described in this study yield TPRs of 85%, TNRs of 86–89% and As of 86–87%. This method does not include drug effects on Na+ channels, which is related to the misclassification of 3 compounds (quetiapine, ranolazine, and lamotrigine – significant Na+ channels blockers at EFTPC). Future work will include this channel. The presented web-based tool is a highly innovative method for an accurate torsadogenic risk assessment. Each assessment required only a few seconds of computational time. Illustration workflow of the web tool Funding Acknowledgement Type of funding source: None