TY - JOUR

T1 - Effect of hydroxychloroquine on the cardiac ventricular repolarization

T2 - A randomized clinical trial

AU - Eveleens Maarse, Boukje C.

AU - Graff, Claus

AU - Kanters, Jørgen K.

AU - van Esdonk, Michiel J.

AU - Kemme, Michiel J.B.

AU - in 't Veld, Aliede E.

AU - Jansen, Manon A.A.

AU - Moerland, Matthijs

AU - Gal, Pim

N1 - Funding Information: The study was funded by the Centre for Human Drug Research, Leiden, The Netherlands. Publisher Copyright: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2022/3

Y1 - 2022/3

N2 - Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - cardiac ventricular repolarization

KW - concentration–effect analysis

KW - electrocardiogram

KW - hydroxychloroquine

KW - QT-interval

U2 - 10.1111/bcp.15013

DO - 10.1111/bcp.15013

M3 - Journal article

C2 - 34327732

AN - SCOPUS:85113718166

VL - 88

SP - 1054

EP - 1062

JO - British Journal of Clinical Pharmacology, Supplement

JF - British Journal of Clinical Pharmacology, Supplement

SN - 0264-3774

IS - 3

ER -