title: Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.
abstract: BACKGROUND
  The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.
  
  
  METHODS
  Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.
  
  
  RESULTS
  Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.
  
  
  CONCLUSIONS
  We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco.
authors.forename: Eskouhie
authors.initials: E
authors.lastname: Tchaparian
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Sambol
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: McCormack
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Wanzira
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mary
authors.initials: M
authors.lastname: Muhindo
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Yale School of Public Health, New Haven, Connecticut.
authors.forename: Nitin
authors.initials: N
authors.lastname: Sukumar
authors.affiliation: Dalarna University, Uppsala, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blessborn
authors.affiliation: Centers for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Tappero
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Abel
authors.initials: A
authors.lastname: Kakuru
authors.affiliation: Dalarna University, Uppsala, Sweden.
authors.forename: Yngve
authors.initials: Y
authors.lastname: Bergqvist
authors.affiliation: Department of Clinical Pharmacy, University of California San Francisco.
authors.forename: Francesca T
authors.initials: FT
authors.lastname: Aweeka
authors.affiliation: Yale School of Public Health, New Haven, Connecticut.
authors.forename: Sunil
authors.initials: S
authors.lastname: Parikh
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044383:Black People; D002675:Child, Preschool; D004359:Drug Therapy, Combination / Q000379:methods; D004983:Ethanolamines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects; D012008:Recurrence; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000493:pharmacokinetics / Q000627:therapeutic use; D014454:Uganda
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000077549:Artemether; D000078102:Lumefantrine
keywords: Malaria; antimalarial; artemisinin combination therapy; lumefantrine; nonlinear mixed effects modeling; pharmacodynamics; population pharmacokinetics; trimethoprim-sulfamethoxazole