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Article Dans Une Revue PLoS Medicine Année : 2018

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

1 Imperial College London
2 ITM - Institute for Tropical Medicine = Institut für Tropenmedizin, Reisemedizin, Humanparasitolgie [Tübingen, Allemagne]
3 Département d'Epidémiologie des Affections parasitaires, Malaria Research and training center Université de Bamako, Mali
4 Institut Pasteur du Cambodge
5 Malaria Research - Department of Microbiology, Tumour and Cell biology [Stockholm, Sweden]
6 Bandim Health Project
7 Department of Women and Children's Health
8 Muhimbili University of Health and Allied Sciences
9 GU - Göteborgs Universitet = University of Gothenburg
10 Université d'Uppsala et Gothenburg
11 UC San Francisco - University of California [San Francisco]
12 YSPH - Yale School of Public Health
13 KEMRI - Kenya Medical Research Institute
14 Medical School [Australian National University - ANU]
15 WEHI - The Walter and Eliza Hall Institute of Medical Research
16 Department of Infectious and Tropical Diseases
17 Epicentre [Paris] [Médecins Sans Frontières]
18 LOMWRU - Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit
19 Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration
20 MERIT - UMR_D 216 - Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique
21 NET - Neuroépidémiologie Tropicale
22 Service des Maladies infectieuses et tropicales [CHU Limoges]
23 Centre for Tropical Medicine and Global Health [Oxford, UK]
24 SMRU - Shoklo Malaria Research Unit [Mae Sot, Thailand]
25 Global Health Division
26 Nagasaki University
27 Centre for Tropical Medicine and Global Health, University of Oxford
28 Mahidol Oxford Tropical Medicine Research Unit
29 University of Oxford
Lesley Workman
  • Fonction : Auteur
Gilbert Lefevre
  • Fonction : Auteur
  • PersonId : 858706
  • IdRef : 033073120
Kamal Hamed
  • Fonction : Auteur
Patrice Piola
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  • PersonId : 942630
Elizabeth Ashley
  • Fonction : Auteur
Michele van Vugt
  • Fonction : Auteur
Ric Price
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  • PersonId : 914108
Farkad Ezzet
  • Fonction : Auteur
Rajesh Bakshi
  • Fonction : Auteur
Karen Barnes
  • Fonction : Auteur
  • PersonId : 901225


Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings A search in PubMed, Embase,, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Conclusions Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Dates et versions

hal-01992875 , version 1 (24-01-2019)



Frank Kloprogge, Lesley Workman, Steffen Borrmann, Mamadou Tékété, Gilbert Lefevre, et al.. Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. PLoS Medicine, 2018, 15 (6), pp.e1002579. ⟨10.1371/journal.pmed.1002579⟩. ⟨hal-01992875⟩
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