Interferences of the autonomic nervous system with drug induced QT prolongation: A point to consider in non-clinical safety studies

Abstract

Introduction QT interval assessment by telemetry has become one of the most useful models in testing strategies adopted for detection of drug induced QT prolongation in non-clinical safety pharmacology studies. This study reports experimental data showing that the autonomic nervous system might influence drug induced QT prolongation. Methods Animals were instrumented with telemetric transmitters and epicardial ECG leads. Effects on QT interval of reference drugs such as thioridazine and terfenadine were analysed with different approaches, the Holzgrefe's probabilistic method, the QT shift method and an individual analysis of beat-to-beat QT/RR pair distribution visualised as points-cloud. Results Two cases of unexpected absence of QT interval prolongation are reported with thioridazine and terfenadine in conscious beagle dogs under conditions of concomitant tachycardia. The pro-arrhythmic properties of these two molecules were unmasked by co-treatment with sympatholytic agents, atenolol and clonidine respectively suggesting that sympathetic activation and/or parasympathetic withdrawal might impair a drug induced QT prolongation. Discussion The apparent absence of changes in the QT interval due to novel drug candidates should be interpreted cautiously under conditions of concomitant tachycardia or elevated heart rate levels in non-clinical safety studies.