Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea.
Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea; Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
Clin Ther. 2019 Nov;41(11):2204-2218. doi: 10.1016/j.clinthera.2019.09.004. Epub 2019 Sep 26.
Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines.
This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated.
Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects.
Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.
塞来昔布是一种选择性环氧化酶-2 抑制剂，广泛用于治疗骨关节炎和类风湿关节炎患者。最近，有研究报道塞来昔布可抑制人类 Ether-a-go-go 相关基因钾通道，但目前尚无强有力的证据表明其在人体中具有这种作用。本研究旨在通过全面的 QT 研究来评估塞来昔布对心脏复极的潜在影响，该研究设计符合相关指南。
这是一项在健康男性和女性受试者中进行的随机、开放标签、阳性和阴性对照、交叉临床研究。每位受试者按照 4 种随机分配顺序中的 1 种，接受以下 3 种干预措施中的 1 种：塞来昔布 400mg 每日 1 次，共 6 天；单次给予莫西沙星 400mg，作为评估检测灵敏度的阳性对照；以及不含任何药物的水，作为阴性对照。在 24 小时内定期采集连续 12 导联心电图和用于药代动力学分析的血样。计算并评估个体 RR 校正 QT 间期（QTcI）和 Fridericia 方法校正 QT 间期（QTcF）。
28 名受试者被分配到 4 种干预序列中的 1 种。塞来昔布对 QTcI 和 QTcF 的最大时间匹配平均影响<5ms，这些值的单侧 95%置信区间上限均未超过 10ms。此外，在多次使用塞来昔布后，没有受试者的绝对 QTcI 值>450ms 或 QTcI 从基线的变化>60ms。QTcI 与高达~2700μg/L 范围内的塞来昔布浓度之间无正相关关系。莫西沙星对 QTcI 和 QTcF 的总体影响足以证明检测的灵敏度。未报告严重不良事件，8 名受试者共报告了 11 例不良事件。
在当前临床应用的最大剂量水平下，塞来昔布不会导致 QT/QTc 间期的临床相关延长。临床试验注册号：NCT03822520。
