Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol
Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol
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DOI：
10.1111/bcp.12201
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发表时间：
2014-03-01
影响因子：
3.4
通讯作者：
Sarapa, Nenad
中科院分区：
文献类型：
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作者：
Darpo, Borje;Karnad, Dilip R.;Sarapa, Nenad
目的 研究男性和女性单次口服剂量 rac-sotalol 后心电图 QT(c) 间期的差异。方法 在单独的基线日和次日单次口服 160mg rac-sotalol 后，记录 28 名男性和 11 名女性的连续 12 导联心电图。在预先指定的时间点提取心电图并上采样至 1000Hz，并在中央心电图实验室中对叠加的中位心搏进行手动分析。使用线性混合效应模型进行浓度-QTc 分析。结果Rac-索他洛尔使男性和女性的心率显着降低。个体校正方法 (QT(c)I) 最有效地消除了 QT(c) 间期的心率依赖性。在基线日的所有时间点，女性的平均 QT(c)I 均延长 10 至 15 毫秒。 Rac-sotalol 显着延长了两性的 QT(c)I。 QT(c)I (QT(c)I) 的最大平均变化在女性中更大（68 毫秒（95% 置信区间 (CI) 59、76 毫秒），而男性则为 27 毫秒（95% CI 22、32 毫秒））。女性的峰值rac-索他洛尔血浆浓度高于男性（平均C-max 1.8gml(-1)（范围1.1-2.8）vs. 1.4gml(-1)（范围0.9-1.9），P = 0.0009）。女性中浓度-QT(c)I 关系的斜率更陡（男性为 30ms/gml(-1)，而男性为 23ms/gml(-1)；P = 0.0135）。结论 该研究提供了证据，证明女性对 rac-sotalol 的内在敏感性高于男性，因为药物引起的心脏复极延迟。
AimTo 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 160mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000Hz 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(c)I) most effectively removed the heart rate dependency of the QT(c) interval. Mean QT(c)I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QT(c)I in both genders. The largest mean change in QT(c)I (QT(c)I) 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 1.8gml(-1) (range 1.1-2.8) vs. 1.4gml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-QT(c)I relationship was steeper in women (30ms per gml(-1)vs. 23ms per gml(-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.