Pharmacokinetic properties of single-dose primaquine in Papua New Guinean children: Feasibility of abbreviated high-dose regimens for radical cure of vivax malaria

Abstract

Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children aged 5-12 years to facilitate development of abbreviated high-dose regimens. Dosing was with food and directly observed, and venous blood samples were drawn over 168 h post-dose. Detailed safety monitoring was performed including hepatorenal function, and hemoglobin and methemaglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid-chromatography/mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentration (Cmax) for both PMQ and CPMQ after last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a 1.0 mg/kg twice daily regimen resulted in a 2.38 and 3.33 times higher Cmax for PMQ and CPMQ, respectively. All predicted median Cmax concentrations were within ranges in adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age-group.