Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium Falciparum Malaria.

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.