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 μg/mL · d [interquartile range (IQR), 126-705 μg/mL · d] versus 816 μg/mL · d [IQR, 536-1150 μg/mL · d] [P = .0001] for sulfadoxine and 620 ng/mL · d [IQR, 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 [IQR, 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 [IQR, 2.73-5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R2 ≥ 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. Clinical Pharmacology & Therapeutics (2006) 80, 582–596; doi: 10.1016/j.clpt.2006.08.016