Richmond Pharmacology Ltd, St George's University of London, Cranmer Terrace, London, United Kingdom.
Br J Clin Pharmacol. 2012 Aug;74(2):296-303. doi: 10.1111/j.1365-2125.2012.04190.x.
The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values, in healthy subjects.
Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers.
The largest time-matched difference in QT(c) I (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day⁻¹) the largest time-matched difference in QT(c) I compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QT(c) greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects.
The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day⁻¹ for 15 days) does not lead to a prolongation of the QT/QT(c) interval above the threshold of regulatory concern.
本研究按照 ICH、E14 关于 QT/QTc 研究的指导原则，评估雷奈酸锶的安全性。其主要目的是比较健康受试者中雷奈酸锶（4 g/天，连续 15 天）与安慰剂在最大时间匹配的平均 QT(c)变化上的差异，从基线到治疗下值。
纳入 96 名健康男性和女性受试者（27.7±7.5 岁），先接受 1 天安慰剂，然后连续 15 天接受超治疗剂量的雷奈酸锶（4 g/天），在 4 个月内进行随机、安慰剂（16 天）和阳性对照（单次给予莫西沙星 400 mg，之前 15 天给予安慰剂）、双盲、双模拟、交叉设计。使用电子卡尺由心脏病专家对心电图进行自动 QT 间期测量，并随后手动进行屏幕复查。
莫西沙星 400 mg 与安慰剂相比，QT(c) I（心率校正的个体 QT 间期）的最大时间匹配差异在给药后 2 小时观察到（平均[95%CI]为 10.62[7.90，13.35]ms）。与安慰剂相比，雷奈酸锶（4 g/天）的 QT(c) I 最大时间匹配差异在给药后 1 小时观察到（平均[90%CI]为 7.54[5.17，9.90]ms）。在研究期间，没有受试者的 QT(c)超过 480 ms。莫西沙星和雷奈酸锶在健康受试者中均耐受良好。
本研究结果表明，给予超治疗剂量的雷奈酸锶（4 g/天，连续 15 天）不会导致 QT/QTc 间期延长超过监管关注的阈值。
