Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications.

Journal article

OBJECTIVE: Our objective was to characterize the pharmacokinetic properties of sulfadoxine-pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations. METHODS: In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry. RESULTS: After adjustment for dose, the area under the concentration-time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 microg/mL x d [interquartile range (IQR), 126-705 microg/mL x d] versus 816 microg/mL x d [IQR, 536-1150 microg/mL x d] [P = .0001] for sulfadoxine and 620 ng/mL x d [IQR, 229-1399 ng/mL x d] versus 1518 ng/mL x d [IQR, 1117-2013 ng/mL x d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL x kg(-1) x d(-1) [IQR, 46.2-132.6 mL x kg(-1) x d(-1)] versus 32.7 mL x kg(-1) x d(-1) [IQR, 22.3-52.2 mL x kg(-1) x d(-1)] for sulfadoxine [P = .0001] and 1.77 L x kg(-1) x d(-1) [IQR, 1.0-3.0 L x kg(-1) x d(-1)] versus 0.85 L x kg(-1) x d(-1) [IQR, 0.62-1.21 L x kg(-1) x d(-1)] for pyrimethamine [P = .0001]; median volume of distribution, 413 mL/kg [IQR, 299-711 mL/kg] versus 372 mL/kg [IQR, 267-488 mL/kg] for sulfadoxine [P = .0021] and 6.28 L/kg [IQR, 3.83-11.24 L/kg] versus 3.83 L/kg [IQR, 2.73-5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R(2) >or= 0.72) of their respective AUCs. CONCLUSIONS: Pharmacokinetic factors may contribute to the increased risk of sulfadoxine-pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with 1 g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.

Authors: Barnes, K; Little, F; Smith, P; Evans, A; Watkins, WM

• Publication status: Published
• Journal: Clinical pharmacology and therapeutics
• Volume: 80
• Issue: 6
• Pages: 582-596
• Publication date: 2006-12-01
• DOI: 10.1016/j.clpt.2006.08.016
• EISSN: 1532-6535
• ISSN: 0009-9236
• Language: English
• Keywords: Area Under Curve; Male; Humans; Child; Malaria, Falciparum; Infant; Child, Preschool; Half-Life; Pyrimethamine; Metabolic Clearance Rate; Regression Analysis; Dose-Response Relationship, Drug; Sulfadoxine; Drug Combinations; Aging; Female; Adult; Adolescent