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 mu g/mL d [interquartile range (IQR), 126-705 mu/mL d] versus 816 mu g/mL d [IQF, 536-1150 mu g/mL d] [P=.0001] for sulfadoxine and 620 ng/mL d [IQF, 229-1399 ng/mL d] versus 1518 ng/mL - d [IQR, 1117-2013 ng/mL - 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 kg(-1) d(-1) [IQF, 46.2-132.6 mL kg(-1) d(-1)] versus 32.7 mL kg(-1) d(-1) [IQR, 22.3-52.2 mL kg(-1) d(-1)] for sulfadoxine [P=.0001] and 1.77 L kg(-1) d(-1) [IQR, 1.0-3.0 L kg(-1) d(-1)] versus 0.85 L kg(-1) d(-1) [IQR, 0.62-1.21 L kg(-1) 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 [IQF, 2.73-5.11 L/kg] for pyrimethamine [P=.0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R-2 >= 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 I g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.