Chloroquine and hydroxychloroquine provoke arrhythmias at concentrations higher than those clinically used to treat COVID‐19: A simulation study

Abstract

The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID‐19), but the reported number of life‐threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 μM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L‐type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch‐clamp system. Using the concentration–inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life‐threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 μM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. WHAT QUESTION DID THIS STUDY ADDRESS? Our objective was to assess the arrhythmogenicity of CQ and HCQ/AZ over a wide range of drug concentrations using a multiscale heart simulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study showed that CQ and HCQ/AZ do not induce fatal arrhythmias even at concentrations much higher than in vitro antiviral half‐maximal effective concentration (EC50) values at which QT prolongation exceeds 150 ms. We also found that estimated free plasma concentrations of CQ and HCQ/AZ achieved by currently used dosing protocols are lower than the antiviral EC50 for these drugs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.

Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation

“…The potencies of chloroquine, hydroxychloroquine and azithromycin against hERG under normal physiological conditions reported here are 1.47 ± 0.07, 3.78 ± 0.18 and 280.1 ± 14.7 μM, respectively, in good agreement with other recent studies (Delaunois et al, 2021; Okada et al, 2021; Szendrey et al, 2021). Some discrepancies with published literature include a lower potency of hydroxychloroquine (23.4 ± 7.9 μM) and lack of acute block by azithromycin reported in Szendrey et al (2021), and a different temperature dependence of potency for hydroxychloroquine in Okada et al (2021), which may be explained by differences in voltage protocols, range of concentrations and recording temperature between the studies.…”

“…The potencies of chloroquine, hydroxychloroquine and azithromycin against hERG under normal physiological conditions reported here are 1.47 ± 0.07, 3.78 ± 0.18 and 280.1 ± 14.7 μM, respectively, in good agreement with other recent studies (Delaunois et al, 2021; Okada et al, 2021; Szendrey et al, 2021). Some discrepancies with published literature include a lower potency of hydroxychloroquine (23.4 ± 7.9 μM) and lack of acute block by azithromycin reported in Szendrey et al (2021), and a different temperature dependence of potency for hydroxychloroquine in Okada et al (2021), which may be explained by differences in voltage protocols, range of concentrations and recording temperature between the studies. In relation to SARS‐CoV‐2, in vitro studies demonstrated EC 50 s for inhibition of viral replication at 24/48 h of 0.72/6.14 μM (240/2000 ng·ml −1 ) for hydroxychloroquine and 5.47/23.9 μM (175/3200 ng·ml −1 ) for chloroquine, meaning these were broadly the therapeutic concentrations aimed for when these drugs were proposed for treatment of COVID‐19 (Yao et al, 2020).…”

“…In relation to SARS‐CoV‐2, in vitro studies demonstrated EC 50 s for inhibition of viral replication at 24/48 h of 0.72/6.14 μM (240/2000 ng·ml −1 ) for hydroxychloroquine and 5.47/23.9 μM (175/3200 ng·ml −1 ) for chloroquine, meaning these were broadly the therapeutic concentrations aimed for when these drugs were proposed for treatment of COVID‐19 (Yao et al, 2020). Our data and that of other recent publications (Delaunois et al, 2021; Okada et al, 2021; Szendrey et al, 2021) therefore suggest significant hERG block, and hence proarrhythmic risk, at doses relevant to COVID‐19. Furthermore, our analysis does not take into account that both chloroquine and hydroxychloroquine have been reported to accumulate in the heart (McChesney et al, 1967), meaning cardiac hERG channels could be exposed to much higher concentrations.…”

“…However, in addition to this, in the heart failure population, individuals with arrhythmia also had significantly up-regulated expression of late sodium current (I NaL ) and down-regulated expression of the rapid delayed rectifier (I Kr ) in both males and females, while females additionally had reduced expression of the chloride current (I Clb ) (Figure 6f). publications (Delaunois et al, 2021;Okada et al, 2021;Szendrey et al, 2021) therefore suggest significant hERG block, and hence proarrhythmic risk, at doses relevant to COVID-19. Furthermore, our analysis does not take into account that both chloroquine and hydroxychloroquine have been reported to accumulate in the heart (McChesney et al, 1967), meaning cardiac hERG channels could be exposed to much higher concentrations.…”

In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine

“…Hence, hydroxylation of CQ's side chain, which reduces its toxicity, does not affect its selectivity nor greatly change its potency at those of the CiPA cardiac ion channels that are sensitive to 4-aminoquinolines. More specifically, our data are also fully in line with those recently obtained on a new generation QPatch II platform, with IC 50 values for racemic HCQ on hERG and K ir 2.1 reaching 17 μM and 30 μM, respectively ( Okada et al, 2021 ). While it is unsure to which extent the differences in IC 50 values are significant, the reasons why the channel sensitivity is inverted in both studies is unclear.…”