title: In silico assessment of drug safety in human heart applied to late sodium current blockers.
abstract: Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I(NaL)) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K(+) current (I(Kr)). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I(Kr)/I(NaL) ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I(NaL) and I(Kr) were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I(Kr) and I(NaL) of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I(NaL)) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Trenor
authors.forename: Julio
authors.initials: J
authors.lastname: Gomis-Tena
authors.forename: Karen
authors.initials: K
authors.lastname: Cardona
authors.forename: Lucia
authors.initials: L
authors.lastname: Romero
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Giles
authors.forename: Javier
authors.initials: J
authors.lastname: Saiz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D003198:Computer Simulation; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015221:Potassium Channels / Q000378:metabolism; D012306:Risk; D012449:Safety; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000009:adverse effects*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D012964:Sodium