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 (AUC(0-∞)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 AUC(0-∞) (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 AUC(0-∞) 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.