A simulation tool to assess the pro-arrhythmic potential of ion channel blockers

Under pathological conditions, such as LQT3, drugs that selectively block late Na⁺ current (I_NaL) exert antiarrhythmic effects by reducing action potential duration (APD). Some of these compounds also block the delayed rectifier K⁺ current (I_Kr) exerting an opposite effect. This study was designed to determine the preclinical safety assessment of ranolazine and an experimental compound (A) with multi-ion channel blocking properties. Using the O´Hara et al. action potential (AP) model for human ventricular myocytes, APDs and QT intervals were calculated in cellular and 1-D tissue simulations, respectively, for different degrees of block of I_NaL and I_Kr under LQT3 (with enhanced I_NaL) conditions. “Safety plots” were represented in a color scale with respective APDs and QT intervals that correspond to different combinations of IC₅₀s for I_Kr and I_NaL of potential drugs. The reference APDs and QT intervals corresponding to LQT3 conditions (enhanced I_NaL), were shortened or prolonged depending on the IC₅₀s of the drugs. Drugs with increasing selectivity for I_NaL block: compound A>; ranolazine yielded 20 and 0% APD or QT interval shortening, respectively, that would be considered safe. This in-silico model appears to be useful in predicting proarrhythmic potential of drugs, and may be suitable for preliminary screening and drug design.