Abstract

QT/QTc interval prolongation reflects delayed cardiac repolarization which can lead to Torsade de Pointes and sudden death. Many antimalarial drugs prolong QT/QTc interval. However, due to confounding factors in patients with malaria, the precise extent of this effect has been found to be highly variable among studies. We compared the effects of dihydroartemisinin-piperaquine phosphate (DHA-PQP) and artemether-lumefantrine (A-L) on QT interval duration in healthy volunteers.

In this randomized, parallel groups, active moxifloxacin- and placebo-controlled study, prolongation of the QT/QTc interval following treatment with DHA-PQP in fasted and fed condition and A-L in fed state was investigated in healthy subjects (n=287; Clinicaltrials.gov: NCT01103830). DHA-PQP resulted in significant mean (95% confidence interval (CI)) maximum increases in QTc Fridericia (QTcF) of 21.0 ms (15.7, 26.4) for DHA-PQP fasted, 35.9 ms (31.1, 40.6) for DHA-PQP high-fat/low-caloric and 46.0 ms (39.6, 52.3) for DHA-PQP high-fat/high-caloric breakfast. For A-L, the largest difference from baseline relative to placebo was 9.9 ms (95% CI: 6.8, 12.9). Increases in QTcF related to maximum plasma concentrations of piperaquine. Moxifloxacin demonstrated assay sensitivity.

Increases in QTcF following DHA-PQP and A-L were clinically relevant. Food increased piperaquine exposure and QTcF interval prolongation emphasizing the need to administer DHA-PQP in the fasting state.

INTRODUCTION

Malaria is a disease that although preventable and tractable still caused approximately 425,000 mortalities in 2016, with most deaths occurring in Africa.¹ The World Health Organization recommends artemisinin-based combination therapies for the treatment of Plasmodium falciparum malaria.² Many antimalarial drugs including artemisinin-based combination therapies have been associated with prolongation of the corrected QT interval (QTc), which reflects a delay in ventricular repolarization during the cardiac cycle.³ Delayed cardiac repolarization can lead to the development of ventricular tachyarrhythmias, most notably Torsade de Pointes, which can be self-terminating but can also degenerate into ventricular fibrillation leading to sudden death.

QT interval is highly influenced by heart rate, physiologically. Assessment of possible QT-prolonging effects of antimalarial drugs in patients is often hampered by the symptoms of malaria most notably fever.³ In the acute phase of the disease, and in addition to fever, stress, anxiety and discomfort may lead to an increase in heart rate. In contrast, during the recovery phase and after starting treatment, heart rate decreases and QT interval lengthens. Therefore since the clinical condition of patients with malaria may induce changes in the QT interval, the effects of antimalarial treatments on cardiac repolarization are ideally studied in healthy subjects.

The fixed-dose artemisinin-based combination therapy of dihydroartemisinin (DHA) and piperaquine phosphate (PQP) is approved in the European Union for the treatment of uncomplicated P. falciparum malaria. Preclinical experiments showed that despite significant blockade of the human ether-a-go-go related channel (hERG), which plays a critical role in cardiac repolarization, DHA-PQP did not appear to induce effects characteristic of Torsade de Pointes, affect hERG trafficking or block sodium channels although it blocked slow-potassium ion currents.⁴ However, in patients with malaria, treatment with DHA-PQP resulted in prolongation of the Fridericia corrected QT interval (QTcF) ranging from 7 to 45 ms.^5-8 Marked QTcF prolongations were also observed for artemisinin-based combination therapies (artemether-lumefantrine [A-L]: 22 ms;⁹ artesunate + mefloquine: 18 ms;¹⁰ artesunate + amodiaquine: 33 ms.⁹). In these studies, electrocardiograms (ECGs) were recorded at various single-time points when plasma drug concentrations were at trough or around presumed peak levels; therefore, the treatment effect on QT interval may have been under- or overestimated.

The present study was conducted in healthy subjects to carefully investigate prolongation of the QT/QTc interval following treatment with DHA-PQP and A-L at the maximum plasma concentrations of their respective active compounds and over the 24 hrs following the last day of drug administrations. The methodology employed was based on that used in thorough QTc studies, which are designed to detect small changes in QTcF.¹¹

RESULTS

Subject Disposition and Demographics

A total of 287 healthy Caucasian subjects were randomized and their disposition in the study is presented in figure 1. Five subjects were withdrawn from the study between  Day –1 and Day 1. Two hundred and eighty-two subjects (174 men and 108 women) received at least one dose of study medication and 279 completed the study. Subjects providing a non-evaluable QT interval were replaced to maintain the pre-established sample size in each group. The mean [range] age and body mass index of the study population were 29.6 [18-50] years and 22.6 [18.0-28.2] kg/m², respectively. Demographic variables (including age, gender, weight and height; data not shown) were similar across groups.

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