Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study

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, espe-cially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with un-complicated malaria, comparing a single dose (15 and 6mg/kg of body weight) administered with water (group 1; n 13), a sin-gle dose (22 and 9mg/kg) with milk (group 2) (n 17), and two daily doses of 22 and 9mg/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 (t1/2) of 1.0 h and predicted medianmaximum plasma concentrations that ranged as high as 57g/liter after the second dose in group 3. The mean NQ elimination t1/2 was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (Vss/F) was 710 liters/kg. Administration of NQwith fat (8.5 g; 615 kJ) versus water was associated with 25 % increased bioavailability. ART disposition was best characterized by a two-compartment mode