Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications.
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.
Barnes
Karen I
KI
Division of Clinical Pharmacology and Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa. kbarnes@uctgsh1.uct.ac.za
Little
Francesca
F
Smith
Peter J
PJ
Evans
Alicia
A
Watkins
William M
WM
White
Nicholas J
NJ
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000378:metabolism; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D011739:Pyrimethamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012044:Regression Analysis; D013413:Sulfadoxine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine