Population pharmacokinetics and pharmacodynamics of lumefantrine in young Ugandan children treated with artemether-lumefantrine for uncomplicated malaria

Eskouhie Tchaparian, Nancy C. Sambol, Emmanuel Arinaitwe, Shelley A. McCormack, Victor Bigira, Humphrey Wanzira, Mary Muhindo, Darren J. Creek, Nitin Sukumar, Daniel Blessborn, Jordan W. Tappero, Abel Kakuru, Yngve Bergqvist, Francesca T. Aweeka, Sunil Parikh

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9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1243-1251
Number of pages9
JournalThe Journal of Infectious Diseases
Volume214
Issue number8
DOIs
Publication statusPublished - 15 Oct 2016

Keywords

  • Antimalarial
  • Artemisinin combination therapy
  • Lumefantrine
  • Malaria
  • Nonlinear mixed effects modeling
  • Pharmacodynamics
  • Population pharmacokinetics
  • Trimethoprim-sulfamethoxazole

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