Centre for Human Drug Research, Leiden, The Netherlands.
Leiden University Medical Centre, Leiden, The Netherlands.
Br J Clin Pharmacol. 2022 Mar;88(3):1054-1062. doi: 10.1111/bcp.15013. Epub 2021 Aug 24.
Hydroxychloroquine has been suggested as possible treatment for severe acute respiratory syndrome-coronavirus-2. Studies reported an increased risk of QTcF-prolongation after treatment with hydroxychloroquine. The aim of this study was to analyse the concentration-dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF-duration and T-wave morphology.
Twenty young (≤30 y) and 20 elderly (65-75 y) healthy male subjects were included. Subjects were randomized to receive either a total dose of 2400 mg hydroxychloroquine over 5 days, or placebo (ratio 1:1). Follow-up duration was 28 days. Electrocardiograms (ECGs) were recorded as triplicate at baseline and 4 postdose single recordings, followed by hydroxychloroquine concentration measurements. ECG intervals (RR, QRS, PR, QTcF, J-Tpc, Tp-Te) and T-wave morphology, measured with the morphology combination score, were analysed with a prespecified linear mixed effects concentration-effect model.
There were no significant associations between hydroxychloroquine concentrations and ECG characteristics, including RR-, QRS- and QTcF-interval (P = .09, .34, .25). Mean ΔΔQTcF-interval prolongation did not exceed 5 ms and the upper limit of the 90% confidence interval did not exceed 10 ms at the highest measured concentrations (200 ng/mL). There were no associations between hydroxychloroquine concentration and the T-wave morphology (P = .34 for morphology combination score). There was no significant effect of age group on ECG characteristics.
In this study, hydroxychloroquine did not affect ventricular repolarization, including the QTcF-interval and T-wave morphology, at plasma concentrations up to 200 ng/mL. Based on this analysis, hydroxychloroquine does not appear to increase the risk of QTcF-induced arrhythmias.
已有研究表明羟氯喹可用于治疗严重急性呼吸综合征冠状病毒 2(SARS-CoV-2)。有报道称,羟氯喹治疗后会增加发生 QTcF 延长的风险。本研究旨在分析羟氯喹的浓度依赖性对心室复极的影响,包括 QTcF 持续时间和 T 波形态。
共纳入 20 名年轻(≤30 岁)和 20 名老年(65-75 岁)健康男性志愿者。志愿者被随机分为 2 组,分别接受为期 5 天的 2400mg 羟氯喹总量或安慰剂(1:1 比例)治疗。随访时间为 28 天。在基线和给药后 4 次单点记录时进行 3 次心电图(ECG)记录,随后测量 ECG 间期(RR、QRS、PR、QTcF、J-Tpc、Tp-Te)和 T 波形态,采用预先指定的线性混合效应浓度-效应模型进行分析。
在 ECG 特征方面,包括 RR、QRS 和 QTcF 间期(P=0.09、0.34、0.25),羟氯喹浓度与 ECG 特征之间均无显著相关性。最大测量浓度下,平均ΔΔQTcF 间期延长不超过 5ms,90%置信区间上限不超过 10ms。羟氯喹浓度与 T 波形态之间也无相关性(形态组合评分 P=0.34)。年龄组对 ECG 特征无显著影响。
在本研究中,羟氯喹在血浆浓度高达 200ng/mL 时不会影响心室复极,包括 QTcF 间期和 T 波形态。基于本分析,羟氯喹似乎不会增加 QTcF 诱导心律失常的风险。