A new electrophysiological protocol combined with mathematical modeling of drug-binding kinetics provided quantitative predictions of action potential modulation that were closer to experimental data.
A novel high-throughput electrophysiological protocol and Markov modeling approach incorporating drug-binding kinetics significantly improves the prediction of drug-induced action potential changes for early safety assessment.
The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new HERG Markov model. The model was then modified to represent the canine rapid delayed rectifier K(+) current at 37°C and carry out AP predictions. Predictions were compared with a simpler model based on conductance reduction and were found to be much closer to experimental data. Improved sensitivity to concentration and pacing frequency variables was obtained when including binding kinetics. Our new electrophysiological protocol is suitable for high-throughput screening and is able to distinguish drug-binding kinetics. The association of this protocol with our modeling approach indicates that quantitative predictions of AP modulation can be obtained, which is a significant improvement compared with traditional conductance reduction methods.
Veroli et al. (Sat,) conducted a other in Drug-induced QT prolongation and Torsade de Pointes risk. New electrophysiological protocol and mathematical modeling of drug-binding kinetics vs. Traditional conductance reduction methods was evaluated on Action potential predictions. A new electrophysiological protocol combined with mathematical modeling of drug-binding kinetics provided quantitative predictions of action potential modulation that were closer to experimental data.