Abstract
The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n = 11) or third (n = 11) trimester with uncomplicated Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0-∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.
Highlights
The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients
Pregnant women with malaria may appear asymptomatic and are at greater risk to develop severe Plasmodium falciparum malaria in low-transmission settings [2], and malaria during pregnancy has been associated with maternal mortality, risk of abortion, stillbirth, neonatal morbidity, and low birth weight [3]
A large pooled analysis showed that day 7 concentrations of Ն200 ng/ml were associated with a cure rate above 98%; 280 ng/ml was used in the present study as the target [11]
Summary
The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. The changes, which include gestational weight gain, plasma protein binding decrease, lipid concentration increase, and increases or decreases in activities of multiple cytochrome P450 enzymes (such as CYP3A4, CYP2C9, and CYP2A6), are often associated with lower drug concentrations, possibly leading to lower antimalarial cure rates in pregnant women with malaria infection [6,7,8]. These changes are often not taken into account in the dosing regimens during pregnancy. The compromised host immunity during pregnancy probably necessitates this relatively higher PK target [11]
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