Pharmacokinetics of amoxicillin in maternal, umbilical cord, and neonatal sera

Abstract

The pharmacokinetics of amoxicillin were studied in umbilical cord and neonatal sera relative to maternal concentrations in prevention of neonatal group B streptococcus infection. The subjects were 44 pregnant women receiving amoxicillin as 1 or 2 g as an intravenous infusion. To measure the concentrations, blood samples were obtained from the mother, the arterial and venous umbilical cord, and the neonate. The pharmacokinetics were characterized by a five-compartment model by using nonlinear mixed-effects (population) modeling. The population estimates for the clearance, central volume of distribution, and the two peripheral maternal volumes of distribution were 19.7 +/- 0.99 liters/h, 6.40 +/- 0.61 liters, and 5.88 +/- 0.83 liters (mean +/- standard error), respectively. The volume of distribution of the venous umbilical cord and the neonatal volume of distribution were 3.40 liters and 11.9 liters, respectively. The pharmacokinetic parameter estimates were used to simulate the concentration-time profiles in maternal, venous umbilical cord, and neonatal sera. The peak concentration in the venous umbilical cord serum was 18% of the maternal peak concentration. It was reached 3.3 min after the maternal peak concentration. The concentration-time profile in neonatal serum was determined by the profile in venous umbilical cord serum, which in turn depended on the profile in maternal serum. Furthermore, the simulated concentrations in maternal, venous umbilical cord, and neonatal sera exceeded the MIC for group B streptococcus for more than 90% of the 4-h dosing interval. In a first approximation, the 2-g infusion to the mother appears to be adequate for the prevention of group B streptococcal disease. However, to investigate the efficacy of the prophylaxis, further studies of the interindividual variability in pharmacokinetics are indicated.

Figures

FIG. 1.

Ratio of arterial umbilical cord serum concentrations to venous umbilical cord serum concentrations as a function of time. The ratio of the arterial umbilical cord serum concentrations to the venous umbilical cord serum concentrations was plotted versus the interval of time between the time of the last antibiotic administration to the mother and the time of birth of the child.

FIG. 2.

Five-compartment model. The structure of the final five-compartment model consists of the central volume of distribution of the mother (V1), the peripheral volumes of distribution of the mother (V2 and V3), the volume of distribution for the venous umbilical cord (V4), and the volume of distribution for the neonate (V5). The k values represent the intercompartmental exchange rate constants.

FIG. 3.

Individual predicted versus observed concentrations of amoxicillin for the central compartment of the mother (V1), the venous umbilical cord compartment (V4), and the neonatal compartment (V5). Scatter plots of the individual predicted concentrations versus the observed concentrations of amoxicillin for 44 patients (V1), 28 measures of the venous umbilical cord (V4), and 25 measures of the arterial umbilical cord with 14 measures for the neonates (V5). The open symbols in V5 represent the neonatal serum concentrations, and the filled symbols represent the arterial umbilical cord concentrations. The three panels show the individual data points and the line of identity (x = y).

FIG. 4.

Simulated concentration-time profiles for the mother, venous umbilical cord, and neonate. The concentration-time profile of amoxicillin in maternal, venous umbilical cord, and neonatal sera was simulated after the administration of a single dose of 2 g amoxicillin infused over 30 min. The simulations were performed with PK parameter estimates based on the final five-compartment model and were carried out for 12 h after the administration of a single dose of antibiotic.