Ornidazole Transfer into Colostrum and Assessment of Exposure Risk for Breastfeeding Infant: A Population Pharmacokinetic Analysis

Abstract

Ornidazole is frequently used for the prevention and treatment of anaerobic infections after caesarean section. There is still a lack of data on the excretion of ornidazole in breast milk. Therefore, the aim of this study was to investigate the transfer of ornidazole into colostrum and to assess the risk of infant exposure to the drug via breast milk. Population pharmacokinetic analysis was conducted using datasets of plasma and milk concentrations obtained from 77 breastfeeding women to examine the excretion kinetics of ornidazole. Various factors that may affect the excretion of ornidazole were investigated. The final model was then used to simulate ornidazole concentration-time profiles in both plasma and milk. The drug exposure in body fluids and the potential risk for breastfeeding were assessed based on the safety threshold. Plasma ornidazole concentration data could be described well by a one-compartment model, and concentrations in breast milk were linked to this model using an estimated milk-to-plasma concentration ratio (MPRcon). Significant variables that influenced drug exposure and MPRcon were identified as total bilirubin levels (TBIL) and postnatal sampling time, respectively. Simulations showed that women with abnormal liver function (TBIL > 17 μmol/L) had higher ornidazole levels in plasma and milk than those with normal liver function (TBIL < 17 μmol/L), but the exposures through colostrum of lactating women from both groups were below the safety threshold. This work provides a simple and feasible strategy for the prediction of drug exposure in breast milk and the assessment of breastfeeding safety.

Keywords: breast milk; infant dose; modeling; ornidazole; population pharmacokinetic.

Figure 1

Concentration–time profiles of ornidazole in plasma (left panel) and breast milk (right panel). Ornidazole concentrations are shown as circles, and observations from the same subject are connected by short lines.

Figure 2

Goodness-of-fit plots of the final model for ornidazole data in plasma (left) and milk (right): (A) observations (DV) versus individual population predictions (IPRED), (B) DV versus population predictions (PRED), (C) conditional weighted residuals (CWRES) versus. PRED, (D) CWRES vs. time after dose (TAD).

Figure 3

Visual predictive check of the final model for ornidazole concentrations in plasma (left) and milk (right): The black circles represent the observations. The dashed and solid red lines represent the 5th, 50th, and 95th percentile of the observed data, respectively. The dashed and solid black lines represent the 5th, 50th, and 95th percentile of the simulated data, respectively. The red and blue shaded areas show the 95% predicted intervals of the 5th–95th percentiles of the simulated data, respectively.

Figure 4

The simulated milk-to-plasma ratio determined through concentrations (A) or exposure (B) of ornidazole: In panel (A), the dashed and black solid lines represent the 2.5th, 50th, and 97.5th percentile of the predicted MPRcon, the blue dashed line represents the horizontal reference line (y = 1), the circles show the Bayesian-corrected measurements of MPRcon, and the red line represents the locally weighted scatterplot smoothing curve. In panel (B), the blue dots show the individual estimates of MPRauc, and the box shows the median, lower, and upper quartiles of the estimates.

Figure 5

The simulated concentration profiles of ornidazole in plasma and breast milk for virtual patients classified by TBIL levels: (A) TBIL < 17 μmol/L and (B) 17 μmol/L < TBIL < 34 μmol/L. The black and green lines represent the 2.5th–97.5th percentile of plasma concentrations and milk concentrations, respectively. The red line indicates the safety threshold of milk concentration.