Whittaker, Dominic G 
ORCID: 0000-0002-2757-5491, Capel, Rebecca A, Hendrix, Maurice ORCID: 0000-0002-6621-7996, Chan, Xin Hui S ORCID: 0000-0002-9941-6975, Herring, Neil ORCID: 0000-0001-8453-6133, White, Nicholas J, Mirams, Gary R ORCID: 0000-0002-4569-4312 and Burton, Rebecca-Ann B ORCID: 0000-0002-0904-3862
(2021)
Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine.
Royal Society open science, 8 (4).
210235-.
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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 <i>Torsade de Pointes</i> (TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet <i>torsade metric score</i>, 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 <i>C</i> <sub>max</sub>) 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 <i>C</i> <sub>max</sub> 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 <i>C</i> <sub>max</sub> 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | arrhythmia, computational biology, electrophysiology, pharmacology |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 09 Apr 2024 14:16 |
| Last Modified: | 09 Apr 2024 15:41 |
| DOI: | 10.1098/rsos.210235 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3180244 |
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