期刊
JOURNAL OF INFECTIOUS DISEASES
卷 214, 期 8, 页码 1243-1251出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiw338
关键词
Malaria; population pharmacokinetics; lumefantrine; artemisinin combination therapy; antimalarial; nonlinear mixed effects modeling; pharmacodynamics; trimethoprim-sulfamethoxazole
资金
- Doris Duke Charitable Foundation [2007055]
- Novartis Pharmaceuticals [COA566A 0940005]
- President's Emergency Plan for AIDS Relief, through the Department of Health and Human Services/Centers for Disease Control and Prevention [U62P024421]
- National Center for HIV, Viral Hepatitis, STD, and TB Prevention
- National Institute of Child Health and Human Development [R01HD068174]
- Global AIDS Program
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.
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