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: Kevin T Batty, Sam Salman, Brioni R Moore, John Benjamin, Sook Ting Lee, Madhu Page-Sharp, Nolene Pitus, Kenneth F Ilett, Ivo Mueller, Francis W Hombhanje, Peter Siba, Timothy M E Davis
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 5 Pg. 2472-84 (May 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22330923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Artemisinins
• Naphthoquinones
• artemisinin-naphthoquine combination

Topics

• Antimalarials (administration & dosage, blood, pharmacokinetics)
• Artemisinins (administration & dosage, blood, pharmacokinetics)
• Biological Availability
• Child
• Chromatography, High Pressure Liquid
• Chromatography, Liquid
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Half-Life
• Humans
• Malaria, Falciparum (blood, drug therapy, parasitology)
• Malaria, Vivax (blood, drug therapy, parasitology)
• Male
• Mass Spectrometry
• Naphthoquinones (administration & dosage, blood, pharmacokinetics)
• Papua New Guinea
• Plasmodium falciparum (drug effects, physiology)
• Plasmodium vivax (drug effects, physiology)