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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 (AUC(0-infinity)) 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.

Artemisinin-based combination therapy (artemether-lumefantrine) is commonly used in pregnant malaria patients. Men, effekten af ​​svangerskabsrelaterede ændringer på eksponering er uklar og svangerskabet har været forbundet med reduceret effektivitet i tidligere studier. Denne undersøgelse har som mål at karakterisere befolkningen af ​​artemether farmakokinetik, dets aktive metabolit dihydroarthemisinin og lumefantrin hos toogtyve rwandiske gravide kvinder i anden og tredje trimester med ukompliceret Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combi­nation of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Venous plasma concentrations were quantified for all three analytes using liquid chro­matography coupled to tandem mass spectroscopy and analysed using nonlinear mixed-effects modelling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 hours, followed by a bi-phasic dis­position model. The median AUC0-∞was 641 μmg / L. Model-based simulations indicated that 11.7% of patients did not reach the target day 7 plasma concentration (280 ng / ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether were 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 hours and the oral clearance of ARM at opportunity 1, increased 1.43 fold, compared at occasion 6. While lumefantrine pharmacokinetic target attainment appeared reassuring in Rwandan pregnant women, especially compared to target achievement in Southeast Asia , larger cohorts will be required to confirm this finding.