title: 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 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 (Cmax) 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 Cmax for PMQ and CPMQ, respectively. All predicted median Cmax 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.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: John
authors.initials: J
authors.lastname: Benjamin
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Leanne J
authors.initials: LJ
authors.lastname: Robinson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Waita
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Batty
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
authors.forename: Inoni
authors.initials: I
authors.lastname: Betuela
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016780:Malaria, Vivax / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D011319:Primaquine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D011319:Primaquine