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

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco.
2
Infectious Diseases Research Collaboration, Kampala, Uganda.
3
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
4
Yale School of Public Health, New Haven, Connecticut.
5
Dalarna University, Uppsala, Sweden.
6
Centers for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia.
7
Department of Clinical Pharmacy, University of California San Francisco.

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

PMID:
27471317
PMCID:
PMC5034953
DOI:
10.1093/infdis/jiw338
[Indexed for MEDLINE]
Free PMC Article
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