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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Joel Tarning, Frank Kloprogge, Patrice Piola, Mehul Dhorda, Sulaiman Muwanga, Eleanor Turyakira, Nitra Nuengchamnong, François Nosten, Nicholas PJ Day, Nicholas J White, Philippe J Guerin, Niklas Lindegardh
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-293) contains supplementary material, which is available to authorized users.

Competing interests

The Wellcome Trust is a UK-based medical research charity and is independent of all drug companies. It has no financial links with the manufacturers of either the diagnostic tests or the drugs used in this study. The authors declared no conflict of interest.

Authors’ contributions

FN, MD, PG, SM, PP and ET planned and conducted the clinical study. NN, NL performed the drug analysis and FK, JT conducted the pharmacokinetic analysis. FK, JT drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content and approved the final version.

Abstract

Background

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.

Conclusion

The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.
Zusatzmaterial
Authors’ original file for figure 1
12936_2012_2493_MOESM1_ESM.pdf
Authors’ original file for figure 2
12936_2012_2493_MOESM2_ESM.pdf
Authors’ original file for figure 3
12936_2012_2493_MOESM3_ESM.pdf
Literatur
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