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

Christian Funck-Brentano, Antonella Bacchieri, Giovanni Valentini, Silvia Pace, Silva Tommasini, Pascal Voiriot, David Ubben, Stephan Duparc, Eric Evene, Mathieu Felices, Marco Corsi, Christian Funck-Brentano, Antonella Bacchieri, Giovanni Valentini, Silvia Pace, Silva Tommasini, Pascal Voiriot, David Ubben, Stephan Duparc, Eric Evene, Mathieu Felices, Marco Corsi

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.

Conflict of interest statement

This study was co-funded by Sigma-tau Industrie Farmaceutiche Riunite s.p.a. and the Medicines for Malaria Venture. A.B., G.V., S.P., S.T. are employees of Sigma-tau. M.C. is a former employee of Sigma-tau. S.D. is an employee of the Medicines for Malaria Venture (MMV) and D.U. is a former employee of MMV. P.V. is CEO of Cardiabase and M.F. is an employee of Phinc Development. E.E. was an employee of SGS-Aster, the contract research organization that performed the study. C.F.-B. was a consultant for Sigma-Tau and MMV.

Figures

Figure 1
Figure 1
Flow chart of subject disposition. Group 1, dihydroartemisinin-piperaquine phosphate (DHA-PQP) low-caloric breakfast; Group 2, artemether-lumefantrine (A-L); Group 3, moxifloxacin; Group 4, DHA-PQP high-caloric breakfast; Group 5, DHA-PQP fasted; Group 6, moxifloxacin. m = male; f = female.
Figure 2
Figure 2
Difference from placebo (Day –1 of respective treatment) in mean change from baseline in QTcF on Day 3. Data are presented as mean and 90% confidence interval. The dotted horizontal line corresponds to the 10 ms threshold. DHA-PQP = dihydroartemisinin-piperaquine phosphate. Square = DHA-PQP low caloric breakfast; triangle = DHA-PQP high caloric breakfast; filled circle = DHA-PQP fasted; open circle = artemether-lumefantrine.

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