Dynamics of drug binding to the hERG channel: an in silico cardiac action potential model for early safety assessment

Pharmaceutical companies are under-pressure to produce potential safe drugs (i.e., no effect on cardiac action potential (AP) and QT interval). Early testing strategies to reduce this risk rely on concentration-effect (C-E) curve data obtained from a panel of heterologously-expressed key ion channels (ICs) using standard IonWorks™ voltage protocols. We had previously presented an in silico canine midmyocardial AP model that uses C-E data to predict changes in AP duration (APD; Hussein L et al., 2010 SPS meeting). We have now investigated whether incorporating the dynamics of drug binding to the hERG channel might improve the accuracy of the model. New IonWorks™ protocols were used to extract binding kinetics of dofetilide, almokalant and cisapride at ~20ºC. Data were fitted with a newly developed hERG model to obtain rate constants for drug binding and unbinding. Rate constants were then incorporated into a new canine IKr model developed at ~37ºC for simulating APs at various concentrations and pacing frequencies. As seen experimentally, AP simulations predict that all three drugs evoked concentration-dependent increase in APD. If instead a traditional C-E curve was employed, results show that APD increases could be significantly under-predicted for cisapride (31% vs. 44% at 1µM) and almokalant (36% vs. 54% at 3µM) at 1.5Hz. Thus, predictivity of the current AP model can be improved with new alternative IonWorks™ protocols. This has the potential to enhance upstream understanding of direct IC modulation of the AP via a rapid cost-effective in silico evaluation.