¹Division of Clinical Pharmacology and Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; and Wellcome-Trust Mahidol University Oxford Tropical Medicine Research Programme, Faculty of Tropical Medicine, Mahidol University, Bangkok.

Correspondence: Karen I. Barnes, MBChB, MMed, Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. E-mail: kbarnes@uctgsh1.uct.ac.za

^*The South East African Combination Antimalarial Therapy (SEACAT) evaluation, within which this study was nested, received core financial support from the United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases (TDR).

Received 24 April 2006; Accepted 28 August 2006.

Abstract

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 g/mL d [interquartile range (IQR), 126-705 g/mL d] versus 816 g/mL d [IQR, 536-1150 g/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.