Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine 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 of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.
© 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.