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

Issued Date

2018-06-01

Resource Type

Article

ISSN

15491676
15491277

DOI

10.1371/journal.pmed.1002579

Other identifier(s)

2-s2.0-85049503104

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

PLoS Medicine. Vol.15, No.6 (2018)

Suggested Citation

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 Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. PLoS Medicine. Vol.15, No.6 (2018). doi:10.1371/journal.pmed.1002579 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46658

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Title

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

Author(s)

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

Other Contributor(s)

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
 UCL
 Karolinska University Hospital
 Universität Tübingen
 Göteborgs Universitet
 CHU de Limoges
 Epicentre
 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

Abstract

© 2018 Kloprogge et al. http://creativecommons.org/licenses/by/4.0/ 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, ClinicalTrials.gov, 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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/46658

Collections

Scopus 2018