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
Y1 - 2018/6
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.
KW - Antimalarials/pharmacokinetics
KW - Artemether, Lumefantrine Drug Combination/pharmacokinetics
KW - Child, Preschool
KW - Dose-Response Relationship, Drug
KW - Ethanolamines/metabolism
KW - Female
KW - Fluorenes/metabolism
KW - Humans
KW - Infant
KW - Infant, Newborn
KW - Malaria, Falciparum/drug therapy
KW - Male
KW - Models, Chemical
KW - Pregnancy
U2 - 10.1371/journal.pmed.1002579
DO - 10.1371/journal.pmed.1002579
M3 - Journal article
C2 - 29894518
AN - SCOPUS:85049503104
SN - 1549-1277
VL - 15
JO - PLoS Medicine
JF - PLoS Medicine
IS - 6
M1 - e1002579
ER -