Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

Abstract

BackgroundSulphadoxine–pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women.MethodsSP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high-performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software.ResultsA two-compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V2) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V2 (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V2 (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant.ConclusionWhile clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp.

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

“…The two lowest values of these parameters were from the groups from Zambia and Mali in which postpartum studies were performed relatively early (36). In contrast, the largest values were from studies (including the present study) that incorporated a nonpregnant matched comparator group (46). This suggests that a significant reduction in SDOX exposure during pregnancy may be missed if comparative postpartum pharmacokinetic data are collected close to delivery.…”

“…In three groups, there was a higher PYR exposure in pregnancy (Mali, Mozambique, and Zambia [36]), two showed no effect of pregnancy (Sudan and Kenya [36,39]), and two showed a lower exposure in pregnancy (PNG and Uganda [34,46]; see Table 8). Nyunt et al have suggested three potential mechanisms that might account for these discrepancies (36).…”

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…”

“…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…”