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.)

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

“…However, one of the main findings of this study was the significant lengthening of the QTcF interval of 16.2 ms in the intervention arm (p < 0.001). This prolongation is comparable with some previous literature for artemether-lumefantrine [23], and it is even longer when compared to other literatures [6,19,33]. No statistically significant QTc prolongation was seen with Bazett's formula in the same treatment arm.…”

“…For a fully accurate comparison between the two arms to be made, ECG recordings obtained at the estimated peak drug concentration in the control arm (4-5 h after the last and 6th dose) would be of high value. Due to the setting of this sub study, and prior studies of the effects on QTc interval from the standard weight based 3-day course of artemether-lumefantrine [6], ECG recordings on day 2 were not performed. The absence of this data curbs the comparisons of absolute QTc interval prolongation between the two arms and constitutes an apparent limitation of this study.…”

“…Also, a recent clinical trial in Congo reported a statistically significant correlation between the QTcF interval, and the concentration of lumefantrine. The Congo study evaluated the efficacy, safety and tolerability of extending treatment with artemether-lumefantrine for 5 days among pregnant and non-pregnant women with uncomplicated P. falciparum malaria [6]. The extended treatment was found to be safe in this study population, and a maximum QTcF interval prolongation of 7.02-8.19 ms was seen.…”

“…Among studies that explored the efficacy and safety of extended ACT, such as artemether-lumefantrine, i.e. the most commonly used artemisinin-based combination for the treatment of uncomplicated P. falciparum malaria in Africa, few have electrocardiographic (ECG) parameters as part of safety reporting [4,6].…”

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

“…The efficacy of the standard treatment regimen for artemether-lumefantrine has been shown to be a function of the region where it is used (Onyamboko et al, 2020). In the high transmission regions of Africa where pregnant women have higher levels of immunity, the standard regimen of artemether-lumefantrine is highly efficacious.…”