Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria

J Infect Dis. 2016 Oct 15;214(8):1243-51. doi: 10.1093/infdis/jiw338. Epub 2016 Jul 28.

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.

Keywords: Malaria; antimalarial; artemisinin combination therapy; lumefantrine; nonlinear mixed effects modeling; pharmacodynamics; population pharmacokinetics; trimethoprim-sulfamethoxazole.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • African Continental Ancestry Group
  • Antimalarials / pharmacokinetics*
  • Antimalarials / therapeutic use*
  • Artemether
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacokinetics*
  • Artemisinins / therapeutic use*
  • Child, Preschool
  • Drug Therapy, Combination / methods
  • Ethanolamines / pharmacokinetics*
  • Ethanolamines / therapeutic use*
  • Female
  • Fluorenes / pharmacokinetics*
  • Fluorenes / therapeutic use*
  • Humans
  • Infant
  • Lumefantrine
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Male
  • Parasitemia / drug therapy
  • Parasitemia / parasitology
  • Plasmodium falciparum / drug effects
  • Recurrence
  • Treatment Outcome
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacokinetics
  • Trimethoprim, Sulfamethoxazole Drug Combination / therapeutic use
  • Uganda

Substances

  • Antimalarials
  • Artemisinins
  • Ethanolamines
  • Fluorenes
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Artemether
  • Lumefantrine