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

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.TI-Pharma: Project nr. D2-104Pharmacolog

Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.

BACKGROUND AND PURPOSE The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. EXPERIMENTAL APPROACH Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect. KEY RESULTS For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively. CONCLUSIONS AND IMPLICATIONS Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans