title: Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?
abstract: Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development.
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Aude
authors.initials: A
authors.lastname: Ouillé
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Julien
authors.initials: J
authors.lastname: Roussel
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roy
authors.affiliation: Centre de Recherche Biologique, CERB, Chemin de Montifault, 18800 Baugy (France).
authors.forename: Serge
authors.initials: S
authors.lastname: Richard
authors.affiliation: Inserm U1046-UMR CNRS 9214, Université de Montpellier, 371 avenue du doyen Gaston Giraud, 34295 Montpellier (France).
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.affiliation: Centre de Recherche Biologique, CERB, Chemin de Montifault, 18800 Baugy (France).
authors.forename: Eric
authors.initials: E
authors.lastname: Martel
authors.affiliation: Centre de Recherche Biologique, CERB, Chemin de Montifault, 18800 Baugy (France).
authors.forename: Pascal
authors.initials: P
authors.lastname: Champéroux
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D003198:Computer Simulation; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors*; D004699:Endocardium / Q000378:metabolism; D006801:Humans; D008955:Models, Cardiovascular; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011689:Purkinje Cells / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers