Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart

Blockade of the delayed rectifier potassium channel current, IKr, has been associated with drug-induced QT prolongation in the electrocardiogram and life-threatening cardiac arrhythmias. However, it is increasingly clear that compound-induced interactions with multiple cardiac ion channels may significantly affect QT prolongation that would result from inhibition of only IKr [Redfern, W.S., Carlsson, L., et al., 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58(1), 32–45]. Such an assessment may not be feasible in vitro, due to multi-factorial processes that are also time-dependent and highly non-linear.Limited preclinical data, IKr hERG assay and canine Purkinje fiber (PF) action potentials (APs) [Gintant, G.A., Limberis, J.T., McDermott, J.S., Wegner, C.D., Cox, B.F., 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J. Cardiovasc. Pharmacol. 37(5), 607–618], were used for two test compounds in a systems-based modeling platform of cardiac electrophysiology [Muzikant, A.L., Penland, R.C., 2002. Models for profiling the potential QT prolongation risk of drugs. Curr. Opin. Drug. Discov. Dev. 5(1), 127–35] to: (i) convert a canine myocyte model to a PF model by training functional current parameters to the AP data; (ii) reverse engineer the compounds’ effects on five channel currents other than IKr, predicting significant IC50 values for INa+,sustainedINa+,sustained and ICa2+,L‐typeICa2+,L‐type, which were subsequently experimentally validated; (iii) use the predicted (INa+,sustainedINa+,sustained and ICa2+,L‐typeICa2+,L‐type) and measured (IKr) IC50 values to simulate dose-dependent effects of the compounds on APs in endocardial, mid-myocardial, and epicardiac ventricular cells; and (iv) integrate the three types of cellular responses into a tissue-level spatial model, which quantifiably predicted no potential for the test compounds to induce either QT prolongation or increased transmural dispersion of repolarization in a dose-dependent and reverse rate-dependent fashion, despite their inhibition of IKr in vitro.