Vancomycin Pharmacokinetics in a Pregnancy Rat Model

Abstract

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R² = 0.978; pup kidney Bayesian, observed versus predicted R² = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h^-1 for trimester 1 dams and 0.75 h^-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 μg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

Keywords: pharmacokinetics; pregnancy; vancomycin.

FIG 1

Animal dosing flow chart for trimester 1 and 3 dams.

FIG 2

(A to D) Best fit plot for observed versus predicted plasma vancomycin concentrations for dam individual/Bayesian (A) and population (B) and pup individual/Bayesian (C) and population (D) utilizing the final 3-compartment trimester-adjusted model.