Andrew J Batey1, Christopher P A Doe. 1. Safety Pharmacology, GlaxoSmithKline, The Frythe, Welwyn, Herts AL6 9AR, UK. Andrew_J_Batey@gsk.com
Abstract
INTRODUCTION: Drug-induced QT prolongation is a major clinical risk factor for arrhythmia induction, particularly torsades de pointes. QT interval is rate dependent, and many formulae exist that attempt to correct QT for changes in heart rate. Most correction factors are acknowledged to overcorrect at high heart rates, undercorrect at low heart rates, and tend to be species specific. Data collected from computerised data acquisition systems are normally reported as means over a given logging period, and so extremes of heart rate are averaged out. Therefore, the aim of this study was to develop a technique for assessing drug-induced changes in the QT/RR relationship, which is simple, suitable for small group sizes, and better able to determine rate-dependent effects of drugs. METHODS: Telemetred beagle dogs (n=4) instrumented for the measurement of electrocardiogram (ECG) were monitored for four separate 20-h periods to define the control QT/RR relationship. Data were binned by RR interval, in 10 ms bins, to produce a control curve. Each dog was treated with vehicle and sotalol (4, 8, 32 mg/kg) in a crossover design to determine whether drug-induced changes in the QT/RR relationship could be detected using the data binning technique. RESULTS: The control QT/RR relationship was curvilinear with a steep section for RR intervals below 580 ms, and was much less steep after this point. Sotalol produced QT prolongation and bradycardia-Fridericia's correction (QTf) reduced the magnitude of this prolongation. The data analysed by the binning technique showed a larger prolongation in QT than was suggested by QTf, and an inverse frequency-dependent response. DISCUSSION: Beat-to-beat analysis and binning allows accurate determination of the QT/RR relationship and assessment of QT prolongation without recourse to mathematical modelling. It also highlights the importance of assessing QT effects in well-trained animals over a range of heart rates.
INTRODUCTION: Drug-induced QT prolongation is a major clinical risk factor for arrhythmia induction, particularly torsades de pointes. QT interval is rate dependent, and many formulae exist that attempt to correct QT for changes in heart rate. Most correction factors are acknowledged to overcorrect at high heart rates, undercorrect at low heart rates, and tend to be species specific. Data collected from computerised data acquisition systems are normally reported as means over a given logging period, and so extremes of heart rate are averaged out. Therefore, the aim of this study was to develop a technique for assessing drug-induced changes in the QT/RR relationship, which is simple, suitable for small group sizes, and better able to determine rate-dependent effects of drugs. METHODS: Telemetred beagle dogs (n=4) instrumented for the measurement of electrocardiogram (ECG) were monitored for four separate 20-h periods to define the control QT/RR relationship. Data were binned by RR interval, in 10 ms bins, to produce a control curve. Each dog was treated with vehicle and sotalol (4, 8, 32 mg/kg) in a crossover design to determine whether drug-induced changes in the QT/RR relationship could be detected using the data binning technique. RESULTS: The control QT/RR relationship was curvilinear with a steep section for RR intervals below 580 ms, and was much less steep after this point. Sotalol produced QT prolongation and bradycardia-Fridericia's correction (QTf) reduced the magnitude of this prolongation. The data analysed by the binning technique showed a larger prolongation in QT than was suggested by QTf, and an inverse frequency-dependent response. DISCUSSION: Beat-to-beat analysis and binning allows accurate determination of the QT/RR relationship and assessment of QT prolongation without recourse to mathematical modelling. It also highlights the importance of assessing QT effects in well-trained animals over a range of heart rates.
Authors: Gong Zhao; Sabrina Serpllion; John Shryock; Eric Messina; Xiaobin Xu; Manuel Ochoa; Luiz Belardinelli; Thomas H Hintze Journal: J Cardiovasc Pharmacol Date: 2008-11 Impact factor: 3.105
Authors: J J Lynch; A W Wilson; L E Hernandez; R A Nelson; K C Marsh; B F Cox; S W Mittelstadt Journal: Br J Pharmacol Date: 2008-06-02 Impact factor: 8.739