Sequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai Adults

Borimas Hanboonkunupakarn, Rob W van der Pluijm, Richard Hoglund, Sasithon Pukrittayakamee, Markus Winterberg, Mavuto Mukaka, Naomi Waithira, Kesinee Chotivanich, Pratap Singhasivanon, Nicholas J White, Arjen M Dondorp, Joel Tarning, Podjanee Jittamala, Borimas Hanboonkunupakarn, Rob W van der Pluijm, Richard Hoglund, Sasithon Pukrittayakamee, Markus Winterberg, Mavuto Mukaka, Naomi Waithira, Kesinee Chotivanich, Pratap Singhasivanon, Nicholas J White, Arjen M Dondorp, Joel Tarning, Podjanee Jittamala

Abstract

Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon. Combining three existing antimalarials in the form of triple ACTs, including dihydroartemisinin (DHA)-piperaquine + mefloquine, is a potential treatment option for multidrug-resistant Plasmodium falciparum malaria. In a sequential open-label study, healthy Thai volunteers were treated with DHA-piperaquine (120 to 960 mg), mefloquine (500 mg), and DHA-piperaquine + mefloquine (120 to 960 mg + 500 mg), and serial symptom questionnaires, biochemistry, full blood counts, pharmacokinetic profiles, and electrocardiographic measurements were performed. Fifteen healthy subjects were enrolled. There was no difference in the incidence or severity of adverse events between the three treatment arms. The slight prolongation in QTc (QT interval corrected for heart rate) associated with DHA-piperaquine administration did not increase after administration of DHA-piperaquine + mefloquine. The addition of mefloquine had no significant effect on the pharmacokinetic properties of piperaquine. However, coadministration of mefloquine significantly reduced the exposures to dihydroartemisinin for area under the concentration-time curve (-22.6%; 90% confidence interval [CI], -33.1, -10.4; P = 0.0039) and maximum concentration of drug in serum (-29.0%; 90% CI, -40.6, -15.1; P = 0.0079). Mefloquine can be added safely to dihydroartemisinin-piperaquine in malaria treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT02324738.).

Keywords: antimalarial agents; healthy subject; pharmacokinetics.

Copyright © 2019 Hanboonkunupakarn et al.

Figures

FIG 1
FIG 1
Changes in the electrocardiogram QTcF (A) and QTcB (B) between baseline and 4 h after administration of DHA-piperaquine alone, DHA-piperaquine + mefloquine, and mefloquine alone. Open circles are observed changes in QTc intervals, and solid red lines are mean values ± 95% confidence intervals.
FIG 2
FIG 2
Ordinary linear regression of QTcF interval prolongations (ΔQTcF) versus piperaquine drug concentrations (A, B, and C) and versus mefloquine drug concentrations (D). (A and B) The relationship between piperaquine drug concentrations and ΔQTcF in healthy volunteers receiving DHA-piperaquine alone (A) and DHA-piperaquine + mefloquine (B). (C) Relationship between piperaquine drug concentrations and ΔQTcF for all volunteers receiving DHA-piperaquine (all arms). (D) Relationship between mefloquine drug concentrations and ΔQTcF for volunteers receiving mefloquine alone. Open circles are observed ΔQTcF at specific drug concentrations. Slopes are displayed as mean regression lines (solid red lines) and 95% confidence intervals (shaded area) and as mean values ± standard errors.
FIG 3
FIG 3
Forest plots showing the geometric mean pharmacokinetic parameter ratios based on 15 individuals (14 for mefloquine) and the corresponding 90% confidence interval for the drugs given alone or in combination with other drugs. AUCLAST represents the area under the concentration-time curve from time zero to the last measurable concentration. Cmax is the maximum concentration, and Tmax is the time to reach the maximum concentration. Solid vertical lines represent no interaction (zero difference), while vertical dashed lines represent a clinically relevant effect of ±25% relative difference. (A) Piperaquine pharmacokinetic parameter ratios when DHA-piperaquine is given alone and in combination with mefloquine. (B) DHA pharmacokinetic parameters when DHA-piperaquine is given alone and in combination with mefloquine. (C) Mefloquine pharmacokinetic parameters when mefloquine is given alone and in combination with DHA-piperaquine.

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