Abstract
Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 nonpregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth and 1, 3, 6, and 12 months. Nonlinear mixed-effects modeling was used to characterize the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range], 3.30 h [1.39 to 7.83 h]) than in nonpregnant women (2.43 h [1.05 to 6.00 h]) (P=0.005). Pregnant women had lower exposures to artemether and dihydroartemisinin than nonpregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to nonpregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and nonpregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure and so could be a promising treatment option in pregnancy in areas with lower rates of malaria transmission and/or emerging drug resistance. (This study has been registered at ClinicalTrials.gov under identifier NCT01916954.).
Highlights
In sub-Saharan Africa, malaria is a major cause of maternal and newborn morbidity and mortality
Previous studies have shown that the standard 3-day treatment in later pregnancy is associated with lower plasma concentrations of artemether, dihydroartemisinin (DHA), and lumefantrine and more rapid elimination of lumefantrine [5,6,7]
Low lumefantrine plasma concentrations are associated with therapeutic failure in the treatment of falciparum malaria [8,9,10]
Summary
In sub-Saharan Africa, malaria is a major cause of maternal and newborn morbidity and mortality. Efficacious antimalarial preventive and treatment regimens can reduce this significantly, but therapeutic choices are limited by concerns over possible toxicity to the developing fetus Because of these concerns, pregnant women are commonly excluded from clinical trials [1]. The absorption of lumefantrine is dose limited, so a longer treatment course has been suggested in order to improve drug exposures in pregnancy [5, 10, 18] The aim of this trial was to assess the tolerability, safety, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine (10 doses over 5 days) compared to the standard 3-day regimen (6 doses over 3 days) in pregnant and nonpregnant African Congolese women with uncomplicated falciparum malaria
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