Exposure of Infants to Isoniazid via Breast Milk After Maternal Drug Intake of Recommended Doses Is Clinically Insignificant Irrespective of Metaboliser Status. A Physiologically-Based Pharmacokinetic (PBPK) Modelling Approach to Estimate Drug Exposure of Infants via Breast-Feeding

Abstract

Isoniazid is a first-line anti-tuberculosis drug recommended for treatment of drug-susceptible Mycobacterium tuberculosis infections. Breast-feeding is not contra-indicated while undergoing isoniazid therapy, even though isoniazid was found to migrate into breast milk, leading to infant drug exposure. Exposure assessment of isoniazid in infants exposed to the drug via breast milk has so far not accounted for the polymorphic expression of the isoniazid metabolising enzyme N-acetyltransferase 2. The aim of this study was to re-visit the safety assessment of maternal isoniazid therapy for infants exposed to the drug via breast milk, while accounting for fast and slow metabolisers in the adult and infant population, as well as for slower metabolism in small infants than in adults. We applied a physiologically-based pharmacokinetic (PBPK) modelling approach to estimate mother and infant external and internal drug exposure non-invasively. Validity of our PBPK models was confirmed through comparison of simulated results with experimental data. Highest recommended oral doses for mothers are daily 300 mg or 900 mg every 3 days. Simulation of maternal intake of 300 mg resulted in oral exposures of 0.58 (95%CI: 0.42-0.69) mg/day and 1.49 (1.22-1.50) mg/day for infants of fast and slow metabolising mothers, respectively. Oral exposures of infants within the first 24 h after maternal intake of 900 mg were 1.75 (1.25-2.06) mg/day and 4.46 (4.00-4.50) mg/day. Maximal drug concentrations in infant plasma ranged between 0.04 and 0.78 mg/L for the two dosing regimens. We therefore conclude that infant exposure to isoniazid via breast milk after maternal drug intake of highest recommended doses is very low. We expect that such low exposure levels most likely do not cause any clinically significant adverse effects in nursed infants.

Keywords: PBPK; breast milk; exposure; infants; isoniazid; pharmacokinetics; tuberculosis.

Figures

FIGURE 1

Schematic representation of the physiologically-based pharmacokinetic (PBPK) models for the lactating woman and breast-fed infant.

FIGURE 2

Validation of the PBPK model of the mother. Simulated concentration-time profiles (black lines) in (1) plasma and (2) breast milk were compared with data points from lactating mothers from four different clinical studies (Lass and Bünger, 1953; Ricci and Copaitich, 1954; Berlin and Lee, 1979; Singh et al., 2007), which either administered (A) 300 mg (Ricci and Copaitich, 1954; Berlin and Lee, 1979; Singh et al., 2007) or (B) 200 mg (Lass and Bünger, 1953) to mothers. Green and blue shadows show 95% confidence intervals of simulated mean estimates for slow and fast metabolisers, respectively.

FIGURE 3

Validation of the PBPK model of the infant. Simulated pharmacokinetics after oral doses of 40 mg where compared with those reported by Rey et al. (2001), who administered 10 mg isoniazid/kg body weight (but did not report the weight of the children). Children in Rey et al. (2001)’s study where 42.5 months old on average (age range: 0.13–196 months). Points with error bars are means and standard errors of the respective means reported by Rey et al. (2001). Black lines show simulated mean concentration estimates with 95% confidence intervals.

FIGURE 4

Concentration-time profiles of isoniazid in (1) plasma of the mother, (2) breast milk, (3) plasma of the infant, and (4) oral doses of the child, for four different mother–infant pairs; (A) mother fast – infant fast, (B) mother fast – infant slow, (C) mother slow – infant fast, (D) mother slow – infant slow. Simulation of maternal oral doses of daily 300 mg, breast-feeding every 2 h, the first breast-feeding event taking place 2 h after drug intake by the mother (“Simulation 1”). Black lines show simulated results for mean clearance estimates. Blue shadows show simulation results for all clearance values laying within the 95% confidence interval of the mean clearance estimate.

FIGURE 5

Concentration-time profiles of isoniazid in (1) plasma of the mother, (2) breast milk, (3) plasma of the infant, and (4) oral doses of the child, for four different mother-infant pairs; (A) mother fast – infant fast, (B) mother fast – infant slow, (C) mother slow – infant fast, (D) mother slow – infant slow. Simulation of maternal oral doses of 900 mg, breast-feeding every 2 h, the first breast-feeding event taking place 2 h after drug intake by the mother (“Simulation 2”). Black lines show simulated results for mean clearance estimates. Blue shadows show simulation results for all clearance values laying within the 95% confidence interval of the mean clearance estimate.