Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig

Abstract

Prolongation of the electrocardiogram QT interval by some, but not all drugs, has been associated with increased incidence of sudden cardiac death. Current preclinical regulatory assays cannot discriminate the arrhythmia liability of these drugs. Consequently, many new medications that prolong the QT interval are not developed despite their potential therapeutic benefit. Alternans (action potential duration alternations) is a measure of cardiac instability in humans and animals associated with the onset of ventricular fibrillation. Due to potential arrhythmia risk from observed QT prolongation, alternans was assessed in the anesthetized guinea pig after azithromycin or chloroquine alone and after combination treatment at clinically relevant concentrations proposed for the management of malaria. Chloroquine alone, but not azithromycin, caused a profound increase in action potential duration but with only minimal effects on alternans (approximately 10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.

Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection

“…15 Azithromycin itself does not usually cause clinically significant prolongation of the QTc interval, 16 but its use in combination with either chloroquine or hydroxychloroquine could theoretically increase the risk of TdP. Reassuringly, an animal model found no evidence of such an interaction, 17 and the combination has been used safely in patients with malaria. 18,19 Nevertheless, given limited experience in patients with COVID-19 and the potential for use of these drugs in patients with cardiac disease or those taking other drugs that delay repolarization, monitoring of the QTc interval at baseline and daily for the duration of treatment is advised, especially if azithromycin is coprescribed.…”

Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

“…Chloroquine is known to delay cardiac repolarization through inhibition of the potassium ion channel [116], increasing the chances of prolonging the electrocardiogram QT interval, while azithromycin does not [117]. The assessment of electrical alternans in an anesthetized guinea-pig showed that there is no additional risk of arrhythmia when azithromycin and chloroquine are used in combination; azithromycin may even be slightly protective of arrythmogenic risk when administered with chloroquine [118]. …”

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

“…In 2007, Fossa and colleagues [Fossa et al 2007] pointed out that current preclinical regulatory assays may poorly determine the arrhythmia liability of drugs associated with QTc interval prolongation. This results in some drugs that link to QTc interval prolongation being dropped prematurely from further development.…”