Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women

A pharmacokinetic-pharmacodynamic meta-analysis

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 & 20 others 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

    Research output: Contribution to journalArticleResearchpeer-review

    2 Downloads (Pure)

    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.

    Original languageEnglish
    Article numbere1002579
    Pages (from-to)1-27
    Number of pages27
    JournalPLoS Medicine
    Volume15
    Issue number6
    DOIs
    Publication statusPublished - 12 Jun 2018

    Fingerprint

    Malaria
    Meta-Analysis
    Pregnant Women
    Pharmacokinetics
    Antimalarials
    Therapeutics
    dihydroartemisinin
    Tablets
    lumefantrine
    artemether
    Appointments and Schedules
    Fats
    Parasitemia
    Falciparum Malaria
    Third Pregnancy Trimester
    Second Pregnancy Trimester
    First Pregnancy Trimester
    PubMed
    Computer Simulation
    Population

    Cite this

    Kloprogge, F., Workman, L., Borrmann, S., Tékété, M., Lefèvre, G., Hamed, K., ... Tarning, J. (2018). Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. PLoS Medicine, 15(6), 1-27. [e1002579]. https://doi.org/10.1371/journal.pmed.1002579
    Kloprogge, Frank ; Workman, Lesley ; Borrmann, Steffen ; Tékété, Mamadou ; Lefèvre, Gilbert ; Hamed, Kamal ; Piola, Patrice ; Ursing, Johan ; Kofoed, Poul Erik ; Mårtensson, Andreas ; Ngasala, Billy ; Björkman, Anders ; Ashton, Michael ; Friberg Hietala, Sofia ; 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 ; Nosten, François ; Ashley, Elizabeth A. ; McGready, Rose ; van Vugt, Michele ; Proux, Stephane ; Price, Ric N. ; Karbwang, Juntra ; Ezzet, Farkad ; Bakshi, Rajesh ; Stepniewska, Kasia ; White, Nicholas J. ; Guerin, Philippe J. ; Barnes, Karen I. ; Tarning, Joel. / Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women : A pharmacokinetic-pharmacodynamic meta-analysis. In: PLoS Medicine. 2018 ; Vol. 15, No. 6. pp. 1-27.
    @article{f12c22aaf3574a7e9b0b724b27ea74bd,
    title = "Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis",
    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.",
    author = "Frank Kloprogge and Lesley Workman and Steffen Borrmann and Mamadou T{\'e}k{\'e}t{\'e} and Gilbert Lef{\`e}vre and Kamal Hamed and Patrice Piola and Johan Ursing and Kofoed, {Poul Erik} and Andreas M{\aa}rtensson and Billy Ngasala and Anders Bj{\"o}rkman and Michael Ashton and {Friberg Hietala}, Sofia and Francesca Aweeka and Sunil Parikh and Leah Mwai and Davis, {Timothy M.E.} and Harin Karunajeewa and Sam Salman and Francesco Checchi and Carole Fogg and Newton, {Paul N.} and Mayfong Mayxay and Philippe Deloron and Faucher, {Jean Fran{\cc}ois} and Fran{\cc}ois Nosten and Ashley, {Elizabeth A.} and Rose McGready and {van Vugt}, Michele and Stephane Proux and Price, {Ric N.} and Juntra Karbwang and Farkad Ezzet and Rajesh Bakshi and Kasia Stepniewska and White, {Nicholas J.} and Guerin, {Philippe J.} and Barnes, {Karen I.} and Joel Tarning",
    year = "2018",
    month = "6",
    day = "12",
    doi = "10.1371/journal.pmed.1002579",
    language = "English",
    volume = "15",
    pages = "1--27",
    journal = "PLoS Medicine",
    issn = "1549-1277",
    publisher = "Public Library of Science (PLoS)",
    number = "6",

    }

    Kloprogge, F, Workman, L, Borrmann, S, Tékété, M, Lefèvre, G, Hamed, K, Piola, P, Ursing, J, Kofoed, PE, Mårtensson, A, Ngasala, B, Björkman, A, Ashton, M, Friberg Hietala, S, Aweeka, F, Parikh, S, Mwai, L, Davis, TME, Karunajeewa, H, Salman, S, Checchi, F, Fogg, C, Newton, PN, Mayxay, M, Deloron, P, Faucher, JF, Nosten, F, Ashley, EA, McGready, R, van Vugt, M, Proux, S, Price, RN, Karbwang, J, Ezzet, F, Bakshi, R, Stepniewska, K, White, NJ, Guerin, PJ, Barnes, KI & Tarning, J 2018, 'Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis', PLoS Medicine, vol. 15, no. 6, e1002579, pp. 1-27. https://doi.org/10.1371/journal.pmed.1002579

    Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women : A pharmacokinetic-pharmacodynamic meta-analysis. / Kloprogge, Frank; Workman, Lesley; Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Ashton, Michael; Friberg Hietala, Sofia; 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; Nosten, François; Ashley, Elizabeth A.; McGready, Rose; van Vugt, Michele; Proux, Stephane; Price, Ric N.; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; White, Nicholas J.; Guerin, Philippe J.; Barnes, Karen I.; Tarning, Joel.

    In: PLoS Medicine, Vol. 15, No. 6, e1002579, 12.06.2018, p. 1-27.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women

    T2 - A pharmacokinetic-pharmacodynamic meta-analysis

    AU - Kloprogge, Frank

    AU - Workman, Lesley

    AU - Borrmann, Steffen

    AU - Tékété, Mamadou

    AU - Lefèvre, Gilbert

    AU - Hamed, Kamal

    AU - Piola, Patrice

    AU - Ursing, Johan

    AU - Kofoed, Poul Erik

    AU - Mårtensson, Andreas

    AU - Ngasala, Billy

    AU - Björkman, Anders

    AU - Ashton, Michael

    AU - Friberg Hietala, Sofia

    AU - Aweeka, Francesca

    AU - Parikh, Sunil

    AU - Mwai, Leah

    AU - Davis, Timothy M.E.

    AU - Karunajeewa, Harin

    AU - Salman, Sam

    AU - Checchi, Francesco

    AU - Fogg, Carole

    AU - Newton, Paul N.

    AU - Mayxay, Mayfong

    AU - Deloron, Philippe

    AU - Faucher, Jean François

    AU - Nosten, François

    AU - Ashley, Elizabeth A.

    AU - McGready, Rose

    AU - van Vugt, Michele

    AU - Proux, Stephane

    AU - Price, Ric N.

    AU - Karbwang, Juntra

    AU - Ezzet, Farkad

    AU - Bakshi, Rajesh

    AU - Stepniewska, Kasia

    AU - White, Nicholas J.

    AU - Guerin, Philippe J.

    AU - Barnes, Karen I.

    AU - Tarning, Joel

    PY - 2018/6/12

    Y1 - 2018/6/12

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85049503104&partnerID=8YFLogxK

    U2 - 10.1371/journal.pmed.1002579

    DO - 10.1371/journal.pmed.1002579

    M3 - Article

    VL - 15

    SP - 1

    EP - 27

    JO - PLoS Medicine

    JF - PLoS Medicine

    SN - 1549-1277

    IS - 6

    M1 - e1002579

    ER -