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    Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria

    Access Status
    Open access via publisher
    Authors
    Salman, S.
    Page-Sharp, Madhu
    Griffin, S.
    Kose, K.
    Siba, P.
    Ilett, K.
    Mueller, I.
    Davis, T.
    Date
    2011
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Salman, Sam and Page-Sharp, Madhu and Griffin, Susan and Kose, Kaye and Siba, Peter M. and Ilett, Kenneth F. and Mueller, Ivo and Davis, Timothy M.E. 2011. Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria. Antimicrobial Agents and Chemotherapy. 55 (11): pp. 5306-5313.
    Source Title
    Antimicrobial Agents and Chemotherapy
    DOI
    10.1128/AAC.05136-11
    ISSN
    0066-4804
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/48138
    Collection
    • Curtin Research Publications
    Abstract

    There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC0-∞s) for artemether and dihydroartemisinin (3,063 and 2,839 μg·h/liter, respectively) were similar to those reported previously in adults with malaria.For lumefantrine, the median AUC0–∞ (459,980 μg·h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC0–∞ weighted on in vitro antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.

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