Female Gender is a Risk Factor for Drug-Induced Long QT and Torsade de Point (TdP) in Anesthetized, Beagle Dogs

Abstract

The female gender is known to be more sensitive to drug-induced long QT and cardiac arrhythmia, based on clinical observations, experimental in vitro data, in isolated rabbit and dog Purkinje fibers, and also in vivo data in rabbits. However, to-date there has been no demonstration of a gender difference in vivo in dogs. As such, the aim of this study was to try and elucidate whether a gender difference is present in this species in vivo. This knowledge is important to drug safety evaluation since conventionally the male dog is the chosen sex for safety pharmacology studies. We evaluated potential gender differences in the following variables in neuromuscular blocked, mechanically ventilated anesthetized dogs: ventricular repolarization (ECG lead II, QT and qtcv; right ventricular endocardial monophasic action potential (MAP), duration at 90% repolarization, (APD90), spatial dispersion of the T wave (Tp-Te), instability of qtend (QT TI: total instability), occurrence of eads and/or tdps. These parameters were derived from continuous beat-to-beat recordings of ECG and MAP signals. 20 female and 18 male dogs were treated with dofetilide (0.05 mg/kg i.v. Infusion over 10 min). At baseline, no statistically significant gender difference was observed on the various parameters, whilst dofetilide infusion produced greater electrophysiological alterations in females than in males. The respective median maximum percentage changes from baseline in females versus males were: heart rate (+3% / +6%, ns), QT (+23% / +14%, p = 0.003), qtcv (+20% / +15%, p = 0.03) and APD90 (+26% / +17%, p = 0.006). Dofetilide tended to differently increase Tp-Te (+40% vs +23%, ns) and QT TI (+150% vs +104%), more in female than in male animals. Additionally, dofetilide infusion elicited more incidences of eads on the MAP signal in female than in male dogs (73% versus 48%). Furthermore, the ikr blocker dofetilide (0.05 mg/kg iv) combined with Iks blocker HMR1556 (0.5 mg/kg iv) elicited tdps in 3 out of 4 female dogs in our preliminary investigations. Similar to man, the present study suggests that the female gender may be a risk factor for drug-induced long QT. Indeed, since significant alterations in additional markers beyond QT interval itself appear to be more pronounced in female dogs and eads occur more frequently in this sex, female dogs could be more sensitive to induction of polymorphic ventricular tachycardia (tdp). As such, consideration should be given to incorporation of female dogs into standard cardiovascular safety evaluations, or at least be the chosen single sex for drug safety evaluation, since the use of males may potentially lead to an underestimate of the QT-related pro-arrhythmogenic risk of a new chemical entity.