Untersuchungen �ber die Diffusion von Isoniazid in den fetalen Kreislauf, das Fruchtwasser und die Muttermilch

Lass, Annaliese; Bünger, Paul

doi:10.1007/bf01477812

Cited by 5 publications

(11 citation statements)

References 3 publications

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“…In contrast, some isoniazid concentrations in breast milk detected in women by Singh et al (2007) were lower than the ones we predicted. For the most part, however, isoniazid concentrations in breast milk simulated were close to those observed in experimental studies by Lass and Bünger (1953), Ricci and Copaitich (1954) and Singh et al (2007). Berlin and Lee (1979) reported one single concentration measurement of isoniazid in breast milk.…”

Section: Resultssupporting

confidence: 83%

“…When simulating the same exposure scenarios with our PBPK model for mothers, approximately two thirds of all data points collected within the experimental studies for isoniazid plasma concentrations lay within the simulated curves for fast and slow metabolising mothers (Figure 2). Isoniazid breast milk concentrations measured by Lass and Bünger (1953) matched well the isoniazid breast milk concentrations predicted with our PBPK model for fast metabolising mothers. Isoniazid breast milk concentrations of two women studied by Ricci and Copaitich (1954) were slightly underpredicted by our model.…”

Section: Resultssupporting

confidence: 71%

“…Lactating women were exposed to an oral dose of 300 mg isoniazid in the studies by Ricci and Copaitich (1954), Berlin and Lee (1979), and Singh et al (2007) and to 200 mg isoniazid in the study by Lass and Bünger (1953). When simulating the same exposure scenarios with our PBPK model for mothers, approximately two thirds of all data points collected within the experimental studies for isoniazid plasma concentrations lay within the simulated curves for fast and slow metabolising mothers (Figure 2).…”

Section: Resultsmentioning

confidence: 80%

“…To validate the PBPK model of the mother, the model-predicted concentration-time profiles of isoniazid in plasma and breast milk were compared with experimental results of four clinical studies: (1) Lass and Bünger (1953), (2) Ricci and Copaitich (1954), (3) Berlin and Lee (1979), and (4) Singh et al (2007). For comparison of simulated results with experimental results, simulated dosing regimens were matched to the clinical studies’ dosing regimens [(2), (3), (4): 300 mg/day, (1): 200 mg/day].…”

Section: Methodsmentioning

confidence: 99%

“…According to the guidelines, breast-feeding is not contra-indicated while undergoing anti-tuberculosis therapy with isoniazid (and any other first-line anti-tuberculosis drug), even though isoniazid was found to migrate into breast milk (Lass and Bünger, 1953; Ricci and Copaitich, 1954; Berlin and Lee, 1979; Singh et al, 2007). The concentrations of isoniazid detected in breast milk were on such low levels, that drug exposure of the infant via breast milk was judged to be insignificant.…”

Section: Introductionmentioning

confidence: 99%

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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

2019

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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.

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Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 71%