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 IC
₅₀
s 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 IC
₅₀
s 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.