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

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

doi:10.1098/rsos.210235

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 Cmax) 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 Cmax 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 Cmax 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.

Highlights

The cinchona alkaloid quinine (QUIN), along with synthetically produced chloroquine (CQ), are quinoline compounds which have been used in the treatment of malaria for decades
The effects of each of the drugs on the action potential duration (APD) were tested at log-spaced concentrations ranging from 0.001 to 100 μM and plotted in terms of the free Cmax, in order to measure the % change in APD90 with concentration
The APD90 as a function of concentration is shown for AZ, CQ, HAL, LOP/RIT, MOX and QUIN in figure 1a, with APs at concentrations equivalent to 1× and 4× free Cmax highlighted

Summary

Introduction

The cinchona alkaloid quinine (QUIN), along with synthetically produced chloroquine (CQ), are quinoline compounds which have been used in the treatment of malaria for decades. CQ and HCQ are diprotic bases which accumulate in acid vesicles including lysosomes over time. Many of their multiple biological activities including their antiviral action are associated with increased vesicle pH [1]. HCQ is used for the treatment of a wide variety of conditions with the majority of use being for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). For these indications, it is often prescribed for use over months to years, and has had a good safety record including in pregnancy [1]

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