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

Clifford TeBay; Jeffrey R McArthur; Melissa Mangala; Nicholas Kerr; Stewart Heitmann; Matthew D Perry; Monique J Windley; Jamie I Vandenberg; Adam P Hill

doi:10.1111/bph.15757

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

Br J Pharmacol. 2022 Jun;179(11):2631-2646. doi: 10.1111/bph.15757. Epub 2022 Jan 27.

Authors

Clifford TeBay¹, Jeffrey R McArthur^{1

2}, Melissa Mangala^{1

3}, Nicholas Kerr^{1

3}, Stewart Heitmann¹, Matthew D Perry^{1

4}, Monique J Windley^{1

3}, Jamie I Vandenberg^{1

3}, Adam P Hill^{1

3}

Affiliations

¹ Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
² Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia.
³ St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
⁴ School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia.

PMID: 34837219
DOI: 10.1111/bph.15757

Abstract

Background and purpose: Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles.

Experimental approach: Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals.

Key results: Chloroquine and hydroxychloroquine blocked hERG with IC₅₀ of 1.47 ± 0.07 and 3.78 ± 0.17 μM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia.

Conclusion and implications: Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.

Keywords: COVID-19; cardiac pharmacology; electrophysiology; ion channels; mathematical modelling; safety pharmacology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acidosis* / chemically induced
Acidosis* / drug therapy
Azithromycin / adverse effects
COVID-19 Drug Treatment*
Chloroquine / adverse effects
Female
Humans
Hydroxychloroquine / adverse effects
Hypokalemia* / chemically induced
Induced Pluripotent Stem Cells*
SARS-CoV-2

Substances

Hydroxychloroquine
Azithromycin
Chloroquine