Key result
Dihydroartemisinin-piperaquine phosphate administered with a high-fat/low-caloric meal resulted in a significantly greater QTcF prolongation compared to artemether-lumefantrine (mean difference 26.0 ms), failing to demonstrate non-superiority.
Why the study?
Antimalarials prolong the QT/QTc interval, but confounding factors in malaria patients have led to highly variable findings across studies regarding the precise extent of this effect.
Do dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine prolong the QTc interval in healthy subjects?
RCT (n=287)
Double-blind and open-label
Randomized
No
Do dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine prolong the QTc interval in healthy subjects?
Mean Difference: 26 (95% CI 22–30)
Absolute Event Rate: 35.9% vs 9.9%
p-value: p=<0.0001
DHA-PQP and A-L cause clinically relevant QTc prolongation in healthy subjects, with DHA-PQP's effect significantly increased by food intake, emphasizing the need for fasting administration.
Advise fasting DHA-PQP administration to limit QTc prolongation; this RCT confirms food augments its effect versus A-L.
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.
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Funck‐Brentano et al. (2019) conducted an RCT in Healthy volunteers (n=287). Dihydroartemisinin-piperaquine phosphate vs. Artemether-lumefantrine was evaluated on Maximum time-matched change in QTcF (MD 26.0 ms, 95% CI 22.0-30.0, p=<0.0001). Dihydroartemisinin-piperaquine phosphate administered with a high-fat/low-caloric meal resulted in a significantly greater QTcF prolongation compared to artemether-lumefantrine (mean difference 26.0 ms), failing to demonstrate non-superiority.
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