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 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.

Regarding “Lactation Status and Studies of Pyrimethamine Pharmacokinetics in Pregnancy”

“…Potential confounders not included in the original modeling reduced, but did not eliminate, between‐site differences in pharmacokinetic parameters. For sulfadoxine, there was an overall threefold higher clearance during pregnancy vs. that after delivery, consistent with other available data2, 3, 4 and reflecting pregnancy‐associated physiological changes 1. Pyrimethamine clearance was, by contrast, 18% lower in pregnancy compared with the postpartum period, with a reduced area under the plasma concentration‐time curve (AUC) after delivery 1…”

“…This suggests strongly that lactating women are not metabolically equivalent to nonpregnant women in the case of pyrimethamine. The reduced pyrimethamine clearance in pregnancy relative to that postpartum, as reported by de Kock et al .,1 does not, therefore, contradict other studies using nonpregnant women as the comparator group that showed increased pyrimethamine clearance and a lower AUC 3, 4…”

“…The lower pregnancy‐associated pyrimethamine clearance reported by de Kock et al 1. would be unusual, as there are few drugs that exhibit this property.…”

“…At present, the primary interest in mammary enzymes is related to breast malignancy rather than drug metabolism, but the expression of CYP enzymes can be upregulated during breastfeeding, which may reduce maternal exposure postpartum. It is of interest that in all studies that compared the disposition of pyrimethamine during pregnancy with that after delivery, including the four substudies analyzed by de Kock et al .,1 the AUC did not return to levels in nonpregnant women in the postpartum period despite variability between studies (see Figure 1). This suggests strongly that lactating women are not metabolically equivalent to nonpregnant women in the case of pyrimethamine.…”

“…In their recent article, de Kock et al 1. re‐analyzed previously published data from a four‐site African study (conducted in Mali, Mozambique, Sudan, and Zambia) that examined the pharmacokinetics of sulfadoxine‐pyrimethamine in women during pregnancy and postpartum.…”