Dr. Durcan, <i>et al</i> reply

Durcan, Laura; Magder, Laurence S.; Petri, Michelle

doi:10.3899/jrheum.160198

Cited by 1 publication

(1 citation statement)

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“…Sumpter et al [6] showed evidence for risk of cardiomyopathy during long-term exposure to high doses of HCQ for the treatment of patients with SLE and RA. The present treatment regime for SLE (generally 200-400 mg d −1 ) [7] includes doses lower than the one originally used to treat arthritis or malaria [8]. Irreversible retinal toxicity is rare at current recommended doses [9,10].…”

Section: Introductionmentioning

confidence: 99%

Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine

et al. 2021

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Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-prolonging anti-infective agents to determine their risk categories for Torsade de Pointes (TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet torsade metric score , a measure of the net charge carried by major currents during the action potential under inhibition of multiple ion channels by a compound. Modelling results for HCQ at a maximum free therapeutic plasma concentration (free C max ) of approximately 1.2 µM (malaria dosing) indicated it is most likely to be in the high-intermediate-risk category for TdP, whereas CQ at a free C max of approximately 0.7 µM was predicted to most likely lie in the intermediate-risk category. Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free C max values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs.

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