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


Moore, BR; Salman, S; Benjamin, J; Page-Sharp, M; Robinson, LJ; Waita, E; Batty, KT; Siba, P; Mueller, I; Davis, TME; Betuela, I
2014-01
Antimicrobial Agents and Chemotherapy
Journal Article
58
1
432-439
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 of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin 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 concentrations (C-max) for both PMQ and CPMQ after the 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 regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher C-max for PMQ and CPMQ, respectively. All predicted median C-max concentrations were within ranges for 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.
AMER SOC MICROBIOLOGY
PLASMODIUM-VIVAX; THAI SUBJECTS; THERAPY; DRUG; CARBOXYPRIMAQUINE; 8-AMINOQUINOLINE; TOLERABILITY; METABOLITES; KNOWLEDGE; RELAPSE
Infection and Immunity
10.1128/aac.01437-13
Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Creation Date 2014-04-30 03:52:41 Last Modified 2015-09-04 11:59:16