A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

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.).

Keywords: antimalarial agents; pregnancy.

Copyright © 2020 Onyamboko et al.

Figures

FIG 1

Flow diagram for pregnant women. Hb, hemoglobin; Pf, P. falciparum; FU, follow-up; RDT, rapid diagnostic test.

FIG 2

Flow diagram for nonpregnant women.

FIG 3

Plots of correlations between Fridericia-corrected QT intervals and predicted lumefantrine concentrations at the time of ECG measurements (A), Bazett-corrected QT intervals and predicted lumefantrine concentrations at the time of ECG measurements (B), and the parasite clearance half-life and the predicted DHA exposure (area under the concentration-time curve from 0 h to infinity) (C).The solid line is the mean regression of observed data, and the shaded areas show the 95% confidence intervals of this estimate. The slope is given as the estimated value ± standard error.

FIG 4

Density of secondary lumefantrine parameters based on a full covariate model investigating categorical pregnancy effects. The solid black line represents no covariate effect, and the dotted black lines represent a covariate effect of ±20%. Tmax is the time to the maximum concentration, Cmax is the maximum concentration, AUC is the total exposure, and half-life is the lumefantrine elimination half-life.

FIG 5

Density of secondary DHA parameters based on a full covariate model investigating categorical pregnancy effects. The solid black line represents no covariate effect, and the dotted black lines represent a covariate effect of ±20%. Tmax is the time to the maximum concentration, Cmax is the maximum concentration, AUC is the total exposure, and half-life is the DHA elimination half-life.