Are women more susceptible than men to drug-induced QT prolongation? Concentration–QT_c modelling in a phase 1 study with oral rac-sotalol

摘要

To study the differences in QT_c interval on ECG in response to a single oral dose of rac-sotalol in men and women.MethodsContinuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160?mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000?Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model.ResultsRac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QT_cI) most effectively removed the heart rate dependency of the QT_c interval. Mean QT_cI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QT_cI in both genders. The largest mean change in QT_cI (ΔQT_cI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean C_max 1.8?μg?ml^?1 (range 1.1–2.8) vs. 1.4?μg?ml^?1 (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQT_cI relationship was steeper in women (30?ms per μg?ml^?1 vs. 23?ms per μg?ml^?1 in men; P = 0.0135).ConclusionsThe study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.