Drug compounds that primarily affect the slow and the fast components of the delayed rectiﬁer current (IKs and IKr, respectively) and the L-type calcium current (ICaL) channels are good candidates for proarrhythmic disorders.
The QT/TdP Risk Screen tool can be used to estimate the proarrhythmic potential risk of drug compounds in preclinical development.
The tool is based on simulations that predict how diﬀerent compounds aﬀect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT interval in a virtual tissue. Multiple channel−drug interactions and state-of-the-art human ventricular action potential models (O’Hara, T., et al. 2011) were used to perform 206.766 cellular and 7072 tissue simulations by blocking the IKs, IKr, and ICaL channels at diﬀerent concentration levels.
The QT/TdP Risk Screen tool’s performance was validated by classifying the proarrhythmic risk of 84 known compounds, 40 of which torsadogenic. Based on these results the new proarrhythmic risk index Tx was developed, and Tx threshold criteria were identified for cellular endocardial, midmyocardial, and epicardial APDs and for the QT interval (Romero et al. 2018).
The tool is easy to use since it only requires the compound’s in vitro IC50 values towards the IKs, IKr and ICaL ion channels and the compound’s test concentration values for which a proarrhythmic potential risk needs to be assessed.
The QT/TdP Risk Screen tool will help you to spot proarrhythmic risks and to identify a safe concentration range for your compounds.