Effects of Dihydroartemisinin-Piperaquine Phosphate and Artemether-Lumefantrine on QTc Interval Prolongation

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.

Reduced Exposure to Piperaquine, Compared to Adults, in Young Children Receiving Dihydroartemisinin‐Piperaquine as Malaria Chemoprevention

“…As we previously reported in pregnant women, we did not observe a significant correlation between piperaquine exposure and QT interval, which may be due to the relatively low peak concentrations seen in these children compared with those reported previously in adults . Prior studies demonstrated correlations between peak piperaquine levels and QTcF, including one study in Cambodian male adults who received a compressed high‐dose 2‐day regimen, with peak piperaquine concentrations of ~ 900 ng/mL and a mean increase in QTcF of 46 msec. In our study of children, standard dosing of DHA‐piperaquine was associated with a modest, but insignificant, QTcB prolongation of 21 and 14 msec at 32 and 104 weeks of age, respectively, a change similar to the 17‐msec change in QTcF we previously reported for pregnant women …”

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data

“…Individual patient-level data were sought from 159 clinical studies (137 published and 22 unpublished at the time of the literature search). Data from 11,109 participants in 53 studies were shared, of which data from 10,452 participants in 43 studies (28 published , 5 subsequently published [46][47][48][49][50], and 10 unpublished) were suitable for inclusion in the meta-analysis (Fig 1 and Tables A and B in S1 Appendix).…”

“…In addition, 68.6% (7,170/10,452) of participants in 30.2% (13/43) of studies had ECGs sent to a centralised facility where specialist staff read ECGs, and in the remainder, ECGs were read at the study site. Only two studies, both of piperaquine in healthy volunteers [48,51], had 24-hour continuous ECG recordings at baseline (Tables C and D in S1 Appendix).…”

Longitudinal Study Based on a Safety Registry for Malaria Patients Treated With Artenimol-Piperaquine in Six European Countries

“…None of the prolongated QTc was associated with any clinically relevant arrhythmic event. Other studies showed less QTc prolongations after APQ treatment in fasting conditions (21.0 ms (15.7-26.4) vs 46.0 ms (39.6-52.3) with high-fat/high caloric breakfast) (5,14,15).…”