Open Access Highly Accessed Research

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

Joel Tarning12*, Frank Kloprogge12, Patrice Piola34, Mehul Dhorda45, Sulaiman Muwanga4, Eleanor Turyakira46, Nitra Nuengchamnong2, François Nosten127, Nicholas PJ Day12, Nicholas J White12, Philippe J Guerin13 and Niklas Lindegardh12

Author Affiliations

1 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

2 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

3 Epicentre, Paris, France

4 Epicentre, Mbarara, Uganda

5 Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA

6 Mbarara, University of Science & Technology, Mbarara, Uganda

7 Shoklo Malaria Research Unit, Mae Sot, Thailand

For all author emails, please log on.

Malaria Journal 2012, 11:293  doi:10.1186/1475-2875-11-293

Published: 22 August 2012

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.

Keywords:
Non-linear mixed effects modeling; Pharmacokinetics; Artemether; Dihydroartemisinin; Pregnancy; Malaria