@article{fdi:010073680,
  title = {{A}rtemether-lumefantrine dosing for malaria treatment in young children and pregnant women : a pharmacokinetic-pharmacodynamic meta-analysis},
  author = {{K}loprogge, {F}. and {W}orkman, {L}. and {B}orrmann, {S}. and {T}ekete, {M}. and {L}efevre, {G}. and {H}amed, {K}. and {P}iola, {P}. and {U}rsing, {J}. and {K}ofoed, {P}. {E}. and {M}artensson, {A}. and {N}gasala, {B}. and {B}jorkman, {A}. and {A}shton, {M}. and {H}ietala, {S}. {F}. and {A}weeka, {F}. and {P}arikh, {S}. and {M}wai, {L}. and {D}avis, {T}. {M}. {E}. and {K}arunajeewa, {H}. and {S}alman, {S}. and {C}hecchi, {F}. and {F}ogg, {C}. and {N}ewton, {P}. {N}. and {M}ayxay, {M}. and {D}eloron, {P}hilippe and {F}aucher, {J}. {F}. and {N}osten, {F}. and {A}shley, {E}. {A}. and {M}c{G}ready, {R}. and van {V}ugt, {M}. and {P}roux, {S}. and {P}rice, {R}. {N}. and {K}arbwang, {J}. and {E}zzet, {F}. and {B}akshi, {R}. and {S}tepniewska, {K}. and {W}hite, {N}. {J}. and {G}uerin, {P}. {J}. and {B}arnes, {K}. {I}. and {T}arning, {J}.},
  editor = {},
  language = {{ENG}},
  abstract = {{B}ackground {T}he fixed dose combination of artemether-lumefantrine ({AL}) is the most widely used treatment for uncomplicated {P}lasmodium falciparum malaria. {R}elatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. {T}he 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. {M}ethods and findings {A} search in {P}ub{M}ed, {E}mbase, {C}linical{T}rials. gov, {G}oogle {S}cholar, conference proceedings, and the {W}orld{W}ide {A}ntimalarial {R}esistance {N}etwork ({WWARN}) pharmacology database identified 31 relevant clinical studies published between 1 {J}anuary 1990 and 31 {D}ecember 2012, with 4,546 patients in whom lumefantrine concentrations were measured. {U}nder 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. {T}he developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. {V}enous 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. {L}umefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. {S}imulations 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). {T}he 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. {T}he absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. {T}hus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. {C}onclusions {O}ur 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. {T}hese 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.},
  keywords = {{MONDE}},
  booktitle = {},
  journal = {{PL}o{S} {M}edicine},
  volume = {15},
  numero = {6},
  pages = {e1002579 [27 p.]},
  ISSN = {1549-1676},
  year = {2018},
  DOI = {10.1371/journal.pmed.1002579},
  URL = {https://www.documentation.ird.fr/hor/fdi:010073680},
}