title: Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a pharmacokinetic study.
abstract: Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua New Guinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n = 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n = 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n = 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t(1/2)) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 μg/liter after the second dose in group 3. The mean NQ elimination t(1/2) was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V(ss)/F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.
authors.affiliation: School of Pharmacy, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Batty
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.forename: John
authors.initials: J
authors.lastname: Benjamin
authors.forename: Sook Ting
authors.initials: ST
authors.lastname: Lee
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Nolene
authors.initials: N
authors.lastname: Pitus
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Francis W
authors.initials: FW
authors.lastname: Hombhanje
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D016780:Malaria, Vivax / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D013058:Mass Spectrometry; D009285:Naphthoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D010966:Plasmodium vivax / Q000187:drug effects* / Q000502:physiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D009285:Naphthoquinones; C543979:artemisinin-naphthoquine combination