Frank Kloprogge1,2, Philippe Guerin1,3 , Mehul Dhorda3,5,6, Sulaiman Muwanga5, Eleanor Turyakira4,5 , Warunee Hanpithakpong2, Nick Day1,2, Nick White1,2, Niklas Lindegardh1,2, François Nosten1,2,7, Patrice Piola1,3,4, Joel Tarning1,2
1 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom, 2 Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand, 3 Epicentre, Paris, France, 4 Mbarara University of Science & Technology, Mbarara, Uganda, 5 Epicentre, Mbarara, Uganda, 6 Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, USA, 7 Shoklo Malaria Research Unit, Mae Sot, Thailand
Background: Pregnancy alters the pharmacokinetic properties of many antimalarial compounds which might result in lower drug exposure and increased risk of treatment failure. The objective of this study was to evaluate the pharmacokinetic properties of Lumefantrine in pregnant and non-pregnant women with uncomplicated P. falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment (Coartem®).
Methods: Dense (25 samples/patient) venous lumefantrine plasma concentration-time data from 26 pregnant women and 17 non-pregnant women was collected. Sparse (5 samples/patient) capillary lumefantrine plasma concentration-time data from another 89 pregnant women was also collected. The population pharmacokinetic properties were evaluated with different distribution, absorption, error and covariate models. Capillary and venous data was modeled separately and simultaneously using an empirical or semi-mechanistic model structure. The final model was compared to a previously published model of pregnant women in Thailand [1].
Results: Lumefantrine absorption was best described by transit-compartment absorption followed by two distribution compartments and first-order elimination from the central compartment. Capillary and venous data could successfully be modeled simultaneously with both a semi-mechanistic model and a more simplified model using a correction factor for capillary concentrations in the error structure. The simplified model using a correction factor was more stable and with no advantage of a more complicated semi-mechanistic model. However, the correction factor could only be estimated on a population level since no patients were sampled for both venous and capillary plasma. The final model included pregnancy as a categorical covariate on inter-compartment clearance and body temperature on mean transit absorption time.
Conclusions: Lumefantrine concentrations were well described in pregnant and non-pregnant women with uncomplicated P. falciparum malaria in Uganda using a population pharmacokinetic approach. The proposed model could successfully link capillary and venous sampling matrices, thereby enabling a comparison of previously published pharmacokinetic studies in different matrices. Lower day 7 concentrations were found in pregnant women compared to non-pregnant women, which might have an impact on treatment efficacy and the development of resistance.
References:
1. Tarning, J., et al., Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother, 2009. 53(9): p. 3837-46.
Reference: PAGE 21 (2012) Abstr 2484 [www.page-meeting.org/?abstract=2484]
Poster: Infection