Pharmacokinetic properties of sulfadoxine-pyrimethamine in pregnant women

Abstract

To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to infinity for SDOX (22,315 versus 33,284 mg x h/liter), NASDOX (801 versus 1,590 mg x h/liter), and PYR (72,115 versus 106,065 microg x h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.

FIG. 1.

Median and interquartile range (IQR) plasma SDOX concentrations in pregnant (solid line and open circles) and nonpregnant (dashed line and closed circles) groups). The symbols “†” and “*” indicate P values of <0.01 or <0.001, respectively, for between-group differences.

FIG. 2.

Structural model used in the final pharmacokinetic analysis. F, bioavailability; k_a, first-order absorption rate constant; V_C/F_SDOX, central compartment volume of distribution for SDOX; V_P/F_SDOX, peripheral compartment volume of distribution for SDOX; Q/F, intercompartmental clearance for SDOX; CL/F_SDOX, clearance of SDOX; CL_M/F, metabolic clearance for SDOX; V/F_NASDOX, V for NASDOX; and CL/F_NASDOX, clearance of NASDOX (fixed at 10 × CL/F_SDOX).

FIG. 3.

Visual predicted check plots showing simulated 10th (dashed line) and 90th (solid line) percentile concentrations and observed concentration (log scale) data versus time (log scale) for SDOX (nonpregnant [A] and pregnant [B]) and NASDOX (nonpregnant [C] and pregnant [D]).

FIG. 4.

Median and IQR plasma PYR concentrations in pregnant (solid line and open circles) and nonpregnant (dashed line and closed circles) groups). The symbols “†” and “*” indicate P values of <0.01 and <0.001, respectively, for between-group differences.

FIG. 5.

Visual predicted check plots showing simulated 10th (dashed line) and 90th (solid line) percentile concentrations and observed concentration data (log scale) versus time (log scale) for PYR (nonpregnant [A] and pregnant [B]).