Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling

Abstract

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n ϭ 15 in each group) and SP-chloroquine (n ϭ 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.

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…”

“…would be unusual, as there are few drugs that exhibit this property. We recently re‐examined our own published pyrimethamine data from pregnant Papua New Guinean women4 and those of other relevant studies with apparently disparate findings, and proposed that lactation status could help to explain between‐study differences. As we outlined,4 national breastfeeding rates in the various studies were high (≥84%) up to 1 year postpartum at the time.…”

“…We recently re‐examined our own published pyrimethamine data from pregnant Papua New Guinean women4 and those of other relevant studies with apparently disparate findings, and proposed that lactation status could help to explain between‐study differences. As we outlined,4 national breastfeeding rates in the various studies were high (≥84%) up to 1 year postpartum at the time. There is evidence (see Supplementary Material ) that breast tissue expresses cytochrome P450 (CYP) genes, especially CYP1B1 which codes for a key enzyme involved in the metabolism of pyrimethamine, as identified in vitro using recombinant CYP enzymes.…”

“…Pyrimethamine median area under the plasma concentration‐time curve (AUC) relative to pregnancy (set at 1.0 shown by the gray line) in studies from Mali (1), Mozambique (2), Sudan (3), and Zambia (4) (♦—♦) from the pooled re‐analysis,1 as well as Papua New Guinea (▲ – – ▲),4, Uganda (• ‐ · · ‐ •),3 and Kenya (▪ ‐ ‐ ▪) 2…”