In Silico Trials for Drug Safety and Efficacy Assessment Using a Novel Human Purkinje Fibre Model

摘要

In silico trials using multiscale and biophysically-detailed human models have proven to be a new powerful tool for proarrhythmic risk prediction. Our goal is to evaluate the consistency between in silico results using a novel human Purkinje model and experimental data obtained from rabbit Purkinje fibres. The effects of Diltiazem, Dofetilide, Risperidone, and Verapamil were evaluated through AP biomarkers, at 1 and 0.2 Hz. Drug-induced effects on the ion channels were simulated through a simple pore-block model using IC₅₀ values and Hill coefficients. Simulation results quantitatively reproduced the drug-induced effects experimentally observed for both Dofetilide and Risperidone. Simulations of Diltiazem and Verapamil correctly reproduced drug-induced effects observed experimentally in the early phase of repolarisation, but they showed AP prolongation instead of shortening. The interplay between Ca^{2+ and K+ current inhibition was identified as the leading cause of the discrepancy. The experimentally observed AP shortening was quantitively matched when not considering the effects on K+ current. In silico trials are a powerful tool for drug safety and efficacy assessment, and their performance requires careful evaluation of data describing drug-ionic current interactions since they critically affect the simulation results.}