Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery

Abstract

Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effectsmodeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight andhematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold forsulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks.This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling ofpharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to bereduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences andelucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, isnecessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.