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

Whittaker, Dominic G.; Capel, Rebecca A.; Hendrix, Maurice; Chan, Xin Hui S.; Herring, Neil; White, Nicholas J.; Mirams, Gary R.; Burton, Rebecca Ann B.

Abstract

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.

Citation

Whittaker, D. G., Capel, R. A., Hendrix, M., Chan, X. H. S., Herring, N., White, N. J., Mirams, G. R., & Burton, R. A. B. (2021). Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine. Royal Society Open Science, 8(4), Article 210235. https://doi.org/10.1098/rsos.210235

• Journal Article Type: Article
• Acceptance Date: Mar 30, 2021
• Online Publication Date: Apr 13, 2021
• Publication Date: Apr 1, 2021
• Deposit Date: Apr 13, 2021
• Publicly Available Date: Apr 15, 2021
• Journal: Royal Society Open Science
• Electronic ISSN: 2054-5703
• Publisher: The Royal Society
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 4
• Article Number: 210235
• DOI: https://doi.org/10.1098/rsos.210235
• Public URL: https://nottingham-repository.worktribe.com/output/5463770
• Publisher URL: https://royalsocietypublishing.org/doi/10.1098/rsos.210235
• Additional Information: Received: 2021-02-09; Accepted: 2021-03-30; Published: 2021-04-14