Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA.
Curr Med Res Opin. 2011 Jul;27(7):1453-63. doi: 10.1185/03007995.2011.585395. Epub 2011 May 24.
This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.
Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis).
For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4-8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc.
Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.
本随机、双盲研究评估了二肽基肽酶-4 抑制剂维格列汀治疗 2 型糖尿病对心脏复极和传导的影响。
健康志愿者（n=101）按 1:1:1:1 比例随机分为维格列汀 100 或 400mg、莫西沙星 400mg（阳性对照）或安慰剂，每日 1 次，连续 5 天。给药后 24 小时内，分别在基线和第 5 天进行 24 小时心电图记录。采用安慰剂校正后，比较每个时间点（时间匹配分析）和整个给药期平均（时间平均分析）的 QT 间期、Fridericia 校正 QT 间期（QTcF）或 Bazett 校正 QT 间期（QTcB）、PR 和 QRS 间期的变化。
对于时间匹配分析，维格列汀治疗的 QTcF 平均变化低于 QTc 延长的预设限值（平均增加<5ms；上限 90%置信区间[CI] <10ms），但维格列汀 100mg 在给药后 1 和 8 小时时除外（上限 90%CI>10ms）。莫西沙星在大多数时间点均显著延长 QTcF，表明该检测方法具有敏感性。无维格列汀或安慰剂治疗的志愿者 QTcF>450ms。维格列汀（100 和 400mg）和安慰剂组 QTcF 增加≥30ms 的发生率相似（4%-8%），明显低于莫西沙星组（39%）。维格列汀或安慰剂组未见 QTcF 增加≥60ms（而莫西沙星组有 1 例）。QTcF/QTcB/QTcB 的时间平均、时间匹配和分类分析显示出相似的结果。药物暴露分析显示维格列汀血浆水平与 QTc 变化无相关性。维格列汀对 PR 或 QRS 间期无影响。尽管这项研究在当前 ICH E14 指南公布前完成，对于时间匹配分析而言效力不足，但结果与维格列汀对 QTc 无影响一致。
在最高日治疗剂量或四倍高剂量时，维格列汀不会延长 QT 间期或影响心脏传导。
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