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

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamics meta-analysis
Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamics meta-analysis
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.
1549-1277
Kloprogge, Frank
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Workman, Lesley
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Bormann, Steffen
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Tékété, Mamadou
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Lefèvre, Gilbert
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Hamed, Kamal
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Piola, Patrice
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Ursing, Johan
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Kofoed, Poul Erik
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Mårtensson, Andreas
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Ngasala, Billy
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Björkman, Anders
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Ashton, Michael
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Hietala, Sofia Friberg
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Aweeka, Francesca
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Parikh, Sunil
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Mwai, Leah
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Davis, Timothy M. E.
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Karunajeewa, Harin
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Salman, Sam
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Checchi, Francesco
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Fogg, Carole
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Newton, Paul N.
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Mayxay, Mayfong
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Deloron, Philippe
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Faucher, Jean François
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Ezzet, Farkad
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Bakshi, Rajesh
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Stepniewska, Kasia
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White, Nicholas J.
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Guerin, Philippe J.
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Barnes, Karen I.
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Tarning, Joel
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Kloprogge, Frank
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Workman, Lesley
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Bormann, Steffen
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Tékété, Mamadou
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Lefèvre, Gilbert
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Hamed, Kamal
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Piola, Patrice
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Ursing, Johan
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Kofoed, Poul Erik
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Hietala, Sofia Friberg
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Aweeka, Francesca
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Parikh, Sunil
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Mwai, Leah
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Davis, Timothy M. E.
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Karunajeewa, Harin
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Salman, Sam
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Checchi, Francesco
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Fogg, Carole
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Newton, Paul N.
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Mayxay, Mayfong
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Deloron, Philippe
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Faucher, Jean François
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Ezzet, Farkad
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Bakshi, Rajesh
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Stepniewska, Kasia
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White, Nicholas J.
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Guerin, Philippe J.
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Barnes, Karen I.
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Tarning, Joel
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Kloprogge, Frank, Workman, Lesley, Bormann, Steffen, Tékété, Mamadou, Lefèvre, Gilbert, Hamed, Kamal, Piola, Patrice, Ursing, Johan, Kofoed, Poul Erik, Mårtensson, Andreas, Ngasala, Billy, Björkman, Anders, Ashton, Michael, Hietala, Sofia Friberg, Aweeka, Francesca, Parikh, Sunil, Mwai, Leah, Davis, Timothy M. E., Karunajeewa, Harin, Salman, Sam, Checchi, Francesco, Fogg, Carole, Newton, Paul N., Mayxay, Mayfong, Deloron, Philippe, Faucher, Jean François, Ezzet, Farkad, Bakshi, Rajesh, Stepniewska, Kasia, White, Nicholas J., Guerin, Philippe J., Barnes, Karen I. and Tarning, Joel (2018) Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamics meta-analysis. PLoS Medicine, 15 (6), [e1002579]. (doi:10.1371/journal.pmed.1002579).

Record type: Article

Abstract

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.

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Accepted/In Press date: 4 May 2018
Published date: 12 June 2018

Identifiers

Local EPrints ID: 433920
URI: http://eprints.soton.ac.uk/id/eprint/433920
ISSN: 1549-1277
PURE UUID: 70ed619b-e416-4490-b1d3-748941402048
ORCID for Carole Fogg: ORCID iD orcid.org/0000-0002-3000-6185

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Date deposited: 06 Sep 2019 16:30
Last modified: 16 Mar 2024 04:40

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Contributors

Author: Frank Kloprogge
Author: Lesley Workman
Author: Steffen Bormann
Author: Mamadou Tékété
Author: Gilbert Lefèvre
Author: Kamal Hamed
Author: Patrice Piola
Author: Johan Ursing
Author: Poul Erik Kofoed
Author: Andreas Mårtensson
Author: Billy Ngasala
Author: Anders Björkman
Author: Michael Ashton
Author: Sofia Friberg Hietala
Author: Francesca Aweeka
Author: Sunil Parikh
Author: Leah Mwai
Author: Timothy M. E. Davis
Author: Harin Karunajeewa
Author: Sam Salman
Author: Francesco Checchi
Author: Carole Fogg ORCID iD
Author: Paul N. Newton
Author: Mayfong Mayxay
Author: Philippe Deloron
Author: Jean François Faucher
Author: Farkad Ezzet
Author: Rajesh Bakshi
Author: Kasia Stepniewska
Author: Nicholas J. White
Author: Philippe J. Guerin
Author: Karen I. Barnes
Author: Joel Tarning

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