title: Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria.
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 (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.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Susan
authors.initials: S
authors.lastname: Griffin
authors.forename: Kaye
authors.initials: K
authors.lastname: Kose
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D000077549:Artemether; D037621:Artemisinins / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D000078102:Lumefantrine; D008288:Malaria / Q000097:blood / Q000188:drug therapy*; D008297:Male
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077549:Artemether; D000078102:Lumefantrine