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Title: Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis
Authors: Frank Kloprogge
Lesley Workman
Steffen Borrmann
Mamadou Tékété
Gilbert Lefèvre
Kamal Hamed
Patrice Piola
Johan Ursing
Poul Erik Kofoed
Andreas Mårtensson
Billy Ngasala
Anders Björkman
Michael Ashton
Sofia Friberg Hietala
Francesca Aweeka
Sunil Parikh
Leah Mwai
Timothy M.E. Davis
Harin Karunajeewa
Sam Salman
Francesco Checchi
Carole Fogg
Paul N. Newton
Mayfong Mayxay
Philippe Deloron
Jean François Faucher
François Nosten
Elizabeth A. Ashley
Rose McGready
Michele van Vugt
Stephane Proux
Ric N. Price
Juntra Karbwang
Farkad Ezzet
Rajesh Bakshi
Kasia Stepniewska
Nicholas J. White
Philippe J. Guerin
Karen I. Barnes
Joel Tarning
Pharmetheus AB
Muhimbili University of Health and Allied Sciences
Bandim Health Project
Institut Pasteur du Cambodge
Kenya Medical Research Institute
Shoklo Malaria Research Unit
University of Western Australia
London School of Hygiene & Tropical Medicine
Universite Paris Descartes
Walter and Eliza Hall Institute of Medical Research
University of Oxford
Danderyd Hospital
Menzies School of Health Research
University of Portsmouth
University of California, San Francisco
Centre de Recherches Pour Le Développement International
Karolinska University Hospital
Universität Tübingen
Göteborgs Universitet
CHU de Limoges
Mahidol University
Karolinska Institutet
Nagasaki University
Novartis International AG
Yale University
Charles Darwin University
Uppsala Universitet
Amsterdam UMC - University of Amsterdam
University of Cape Town
Kolding Sygehus
WorldWide Antimalarial Resistance Network
University of Sciences
Novartis Pharmaceuticals
Wellcome Trust Research Unit
WorldWide Antimalarial Resistance Network
Myanmar Oxford Clinical Research Unit
World Wide Antimalarial Resistance Network (WWARN)-Asia Regional Centre
WorldWide Antimalarial Resistance Network
Afya Research Africa
University of Health Sciences
Keywords: Medicine
Issue Date: 1-Jun-2018
Citation: PLoS Medicine. Vol.15, No.6 (2018)
Abstract: © 2018 Kloprogge et al. 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.
ISSN: 15491676
Appears in Collections:Scopus 2018

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