Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects
Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects
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DOI：
10.1111/cts.12452
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发表时间：
2017-05-01
影响因子：
3.9
通讯作者：
Jenkins, R.
中科院分区：
文献类型：
--
作者：
Astruc, B.;Jenkins, H.;Jenkins, R.
这项I期、随机、4期、4序列、双盲、主动和安慰剂对照的交叉研究评估了伏诺哌赞对健康受试者QT/QTc间期的影响。受试者接受单次口服vonoprazan 40 mg， vonoprazan 120 mg， moxiflo沙星400 mg（阳性对照/开放标签）和安慰剂。主要终点为时间匹配、安慰剂校正、基线校正的平均fridercia校正QT间期（ddQTcF）。在64名受试者中（平均年龄37.8岁，50%为男性），63名受试者接受了所有四种方案。一名受试者因非药物相关的扁桃体炎不良事件而停药。建立检测灵敏度；莫西沙星给药后1.5 ~ 12 h， ddQTcF的单侧95%置信区间（CI）下界为bb0.5 ms。对于两种剂量的vonoprazan，单侧95% CI上限ddQTcF不超过10 ms。血浆vonoprazan浓度与ddQTcF升高无相关性。Vonoprazan耐受性良好。无严重不良事件/死亡报告。
This phase I, randomized, 4-period, 4-sequence, double-blind, active- and placebo-controlled, crossover study assessed the effects of vonoprazan on the QT/QTc interval in healthy subjects. Subjects received single oral doses of vonoprazan 40 mg, vonoprazan 120 mg, moxifloxacin 400 mg (positive control/open label), and placebo. The primary end point was time-matched, placebo-corrected, baseline-adjusted mean Fridericia-corrected QT interval (ddQTcF). Of 64 subjects (mean age, 37.8 years; 50% male), 63 received all four regimens. One subject discontinued due to nondrug-related adverse event of tonsillitis. Assay sensitivity was established; lower bound of the one-sided 95% confidence interval (CI) for ddQTcF was >5 ms between 1.5 and 12 h following moxifloxacin administration. For both doses of vonoprazan, the one-sided upper 95% CI ddQTcF did not exceed 10 ms. There was no correlation between plasma vonoprazan concentrations and increases in ddQTcF. Vonoprazan was well tolerated. No severe adverse events/deaths were reported.