title: Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart.
abstract: Blockade of the delayed rectifier potassium channel current, I(Kr), 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 I(Kr) [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, I(Kr) 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 I(Kr), predicting significant IC(50) values for I(Na+), sustained and I(Ca2+), L-type , which were subsequently experimentally validated; (iii) use the predicted (I(Na+), sustained and I(Ca2+), L-type) and measured (I(Kr)) IC(50) 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 I(Kr) in vitro.
authors.affiliation: The BioAnalytics Group LLC, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Bottino
authors.forename: R Christian
authors.initials: RC
authors.lastname: Penland
authors.forename: Andrew
authors.initials: A
authors.lastname: stamps
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.forename: Bérengère
authors.initials: B
authors.lastname: Dumotier
authors.forename: Anna
authors.initials: A
authors.lastname: Georgiva
authors.forename: Gabriel
authors.initials: G
authors.lastname: Helmlinger
authors.forename: G Scott
authors.initials: GS
authors.lastname: Lett
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D003198:Computer Simulation; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008133:Long QT Syndrome / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011690:Purkinje Fibers / Q000187:drug effects / Q000503:physiopathology; D016171:Torsades de Pointes / Q000188:drug therapy*
chemical_list: D000889:Anti-Arrhythmia Agents; D007473:Ion Channels