Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda
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Date
2012
Journal Title
Journal ISSN
Volume Title
Publisher
Malaria journal
Abstract
Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight.
Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission.
Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug
exposure increases the risk of treatment failure. The objective of this study was to evaluate the population
pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with
uncomplicated P. falciparum malaria in Uganda.
Methods: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of
pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three
days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified
using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population
pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different
disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental
analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.
Results: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption
model with sequential zero-order and transit-compartment absorption followed by a simultaneous
one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data.
Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An
approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by
non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug
and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches
Description
Keywords
Non-linear mixed effects modeling, Pharmacokinetics, Artemether, Dihydroartemisinin
Citation
Tarning, J., Kloprogge, F., Piola, P., Dhorda, M., Muwanga, S., Turyakira, E., ... & Lindegardh, N. (2012). Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. Malaria journal, 11(1), 1-12.