Sex differences in drug-induced changes in ventricular repolarization

• There were no sex differences in QTc changes for any of the four drugs.
• There were few sex differences in dofetilide-induced J-Tpeakc and Tpeak–Tend changes.
• Dofetilide sex differences were consistent with baseline sex differences.
• There were no systematic sex differences in drug-induced ECG changes in the study.
• Higher torsade risk in women compared to men may not be due to a larger concentration-dependent QTc prolongation.

IntroductionHeart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs.Methods and resultsTwenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p = 0.045) but lesser Tpeak–Tend prolongation (p = 0.006) and lesser decrease of T wave amplitude (p = 0.003) in women compared to men.ConclusionsThere were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation.