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

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.

Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

“…In contrast, for moxifloxacin, no significant change in potency was observed between physiological temperature and 42 °C (Alexandrou et al 2006 ). Similarly, our investigations showed that febrile temperature significantly increased the potency of azithromycin as compared to physiological temperatures, while for chloroquine and hydroxychloroquine, potency was significantly reduced (TeBay et al 2021 ). Further insights into the effect of temperature on hERG block can be gleaned from experiments performed at subfebrile temperatures, which are far more common in the literature.…”

“…The authors also demonstrated that block by N-methyl-verapamil, a permanently charged analogue of verapamil, was not sensitive to changes in pH, confirming that the effect on block was specifically due to the charge on the drug molecule (Zhang et al 1999 ). Similar explanations have also been posed for other drugs such as flecainide (Du et al 2011 ), ibogaine (Thurner et al 2014 ), fentanyl (Tschirhart and Zhang 2020 ) and hydroxychloroquine (TeBay et al 2021 ) supporting the case that this is a common mechanism for the effect of pH on a drug’s potency to bock ERG.…”

“…Here we will focus on studies that have specifically addressed potassium dependence of a drug’s potency to block hERG. Across the literature, reports of the influence of K + on potency to block hERG across drugs is broadly consistent, with increasing extracellular potassium reducing the potency of block (Barrows et al 2009 ; Busch et al 1998 ; Lin et al 2007 , 2008 , 2005c ; Lin and Papazian 2007 ; Mergenthaler et al 2001 ; TeBay et al 2021 ; Wang et al 1997 ; West et al 1997 ; Yang et al 2004 ) and decreased potassium concentration increasing potency of block (Lin et al 2005a ; TeBay et al 2021 ; Tschirhart and Zhang 2020 ). Two potential mechanisms have been proposed to explain this.…”

“…Furthermore, the literature that does exist presents a somewhat inconsistent narrative. Increased extracellular Mg 2+ has been shown to increase the potency of hERG block for multiple compounds (Po et al 1999 ; TeBay et al 2021 ), whereas reduced internal Mg 2+ was found to reduce the potency of quinidine (Yang et al 1997 ). Conversely, concentrations of extracellular Ca 2+ between 0.1 and 10 mM did not modify the block of either quinidine or cisapride (Barrows et al 2009 ).…”

“…In the latter case, early experiments showed that a reduction in pH to 6.8 could significantly reduce hERG block by dofetilide (West et al 1997 ). Across numerous subsequent reports, there is broad consensus that extracellular acidification reduces hERG block by a range of compounds (Du et al 2011 ; Lin et al 2005a , b , 2008 ; TeBay et al 2021 ; Thurner et al 2014 ; Tschirhart and Zhang 2020 ; Wang et al 2016 ; Zhang et al 1999 ), with alkalisation enhancing drug block (Lin et al 2005a ; Thurner et al 2014 ; Tschirhart and Zhang 2020 ; Zhang et al 1999 ). There is however some complexity to this relationship since quite different results were seen when the extracellular solution was acidified using sodium acetate rather than hydrochloric acid.…”