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Reverse engineering of drug induced QT(c) interval prolongation: Towards a systems pharmacology approach

Promotor: M. Danhof Co-promotor: O.E. Della Pasqua

V.F.S. Dubois
02 mei 2017
Thesis in Leiden Repository

QT prolongation and the risk of ventricular arrhythmias in humans remain a major concern during drug development despite the advancement of numerous methodologies to detect the potential for drug-induced changes in cardiac conductivity and the availability of regulatory guidelines for the evaluation of pro-arrhythmic drug effects. Numerous in vitro and in vivo studies are conducted before new molecules are progressed into humans; for many of these compounds extrapolation from non-clinical experimental data suggests no clinically relevant effects. Still a vast number of compounds show pro-arrhythmic signals during clinical development. Current practice and decision making in cardiovascular safety research in R&D relies on the use of independent experimental filters to assess pro-arrhythmic risk: a) ion or hERG-channel specific assays in which binding or inhibition are assessed in vitro, b) functional measures of drug effect on action potential or tissue conductivity, c) heart-rate corrected QT interval (QTc) prolongation in non-clinical species in vivo, and finally d) QT prolongation in humans.