Population pharmacokinetics of artemether, dihydroartemisinin and lumefantrine in Rwandese pregnant women treated for uncomplicated Plasmodium falciparum malaria [PublishAheadOfPrint]

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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 of second (n=11) and third trimester (n=11) with uncomplicated 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 data analyzed 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- for lumefantrine was 641 h.mg/L. 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. Pharmacokinetics of artemether was time-dependent and the auto-induction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 hours. The typical oral clearance, which started at 475.7 L/hr, increased 1.43 fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.