Immunomodulating and antineoplastic agents

4.10.1

Azathioprine and 6-mercaptopurine

Azathioprine (AZA) is quickly metabolized to 6-mercaptopurine (6-MP), which has a lower oral bioavailability. 6-MP, in turn, is transformed into the active metabolites 6-thioguanine-nucleotide (6-TGN) and 6-methylmercaptopurine-nucleotide (6-MMPN).

Misgivings have frequently been raised about the use of AZA and 6-MP during breastfeeding due to its cytotoxic properties. Meanwhile, there are many reports available in which not only the development and growth of the infants, but also the concentrations of 6-MP and the active metabolites in the mother’s milk were studied in the infant’s and the mother’s serum and, to some extent, even the genotype of thiopurine methyltransferase (TPMT) in the mother. Gene mutations can diminish the activity of TPMT, which can lead to an increase of toxic metabolites and an increase of side effects, e.g. bone marrow suppression.

The majority of observations of over 50 breastfed infants have not presented any toxic effects ( , , , , , ). Only one of six children demonstrated a temporary bone marrow dysfunction ( ). Unfortunately, neither the maternal TPMT genotype nor further details were reported.

In one publication, the maternal AZA dose was between 50 and 200 mg/day. The metabolite 6-MP was not detected in the mother’s milk, so that a relative infant dose of 0.09% was calculated ( ). considered this method to be insufficient and determined the 6-MP and 6-TGN concentrations in the serum of four mother–child pairs. While therapeutic levels were reported in the mothers, detection of the substance in the children was not successful. All of the mothers had the normal TPMT genotype. also found very low concentrations of 6-MP in the milk and could not detect 6-MP and 6-TGN in the children’s serum. Based upon eight mother–child pairs (maternal dose between 75 and 200 mg daily and the normal TPMT genotype), a child’s maximum intake through the milk was calculated at <0.008 mg/kg per 24 hours ( ). The metabolite, 6-MMPN, in the mother’s and child’s sera was also identified. While therapeutic concentrations were measured in the mother’s serum, the child’s serum levels were below detection ( ). The development of 15 children of mothers who took an average AZA dose of 150 mg daily was compared with a similar-sized group of children from healthy mothers. The duration of breastfeeding was between 6 and 8 months and the follow-up observation was for 3.6 and 4.7 years. There were no differences in motor and intellectual development nor the frequency of in-patient hospital stays or serious infections. Somewhat more frequently, greater than two common infections per year and conjunctivitis were observed in the children of mothers treated with AZA ( ).

The positive experiences to date primarily comprises of mothers without the TPMT gene mutation. Therefore, safety cannot be concluded for carriers of polymorphisms with reduced TPMT activity. Because routine assessment of the genotypes is too expensive, some experts recommend that a complete blood count and liver enzymes be determined with all children.

4.10.2

Selective immune suppressants

There is no information concerning the use of the teratogenic (see Chapter 2.12.3 ) mycophenolate mofetil (MMF) or mycophenolic acid (MPA) during breastfeeding.

In adults, the half-life of cyclosporine metabolites is 19 hours. All of the reports on the use of cyclosporine or cyclosporine A (CyA) during breastfeeding demonstrate normal infant growth (see, for example, ). Three case series ( , , ) and individual case reports (for example, , ), with approximately 20 mother–child pairs, reported very different drug concentrations in human milk from 14–1,016 μg/L CyA. The serum concentrations of the mothers varied between 49 and 903 μg/L. In the majority of cases, the concentrations in the children’s blood were below the detection limit. However, in one case, 131 μg/L – about 70% of the maternal concentration – was reported ( ). The mother of this clinically unremarkable child with a therapeutic CyA serum concentration (131 μg/L), showed a wide range of CyA levels in her blood and sometimes high values However, the concentration of the drug in her milk was relatively low. Summarizing all the available values in the milk, a relative dose of about 2% for the child can be expected. A later finding calculates only 0.33% of the maternal weight adjusted dose ( ). Neither with this child nor with others was CyA detectable in the child’s serum ( , ).

In a group of 25 pregnancies treated with the immune suppressant, tacrolimus (after a liver transplant), the initial milk samples after birth were measured to average 0.6 μg/L. Accordingly, a fully breastfed child would receive less than 0.1 μg/kg/day. This represents a relative dose of about 0.1% ( ). even calculates only 0.02%. By contrast, calculates a relative dose of 0.5%. In the serum of three fully-breastfed infants of mothers receiving tacrolimus treatment, no tacrolimus was detectable. The children showed age-appropriate development, which was followed to the age of 2.5 ( ). One year later, provided a longer follow-up of six children exposed to tacrolimus through breastfeeding. The median duration of follow-up was 8.5 months (range 2–30 months). No adverse effects related to tacrolimus were noted and developmental milestones were within the expected ranges. The levels of tacrolimus measured in four neonates (15–27 days after birth) were undetectable. Seven additional children with exposure during breastfeeding grew normally ( ). Recently, assessed 14 women taking tacrolimus during pregnancy and lactation, and their 15 infants. Eleven of the children were exclusively breast-fed. Maximum estimated absorption from breast milk was 0.23% of weight-adjusted maternal dose. The authors concluded that ingestion of tacrolimus by infants via breast milk is negligible.

The amount of tacrolimus excreted in the breast milk over a 12-hour steady-state dosing interval was determined in one patient treated with 1.5 mg orally twice daily ( ). Infant exposure to tacrolimus through the breast milk was estimated to be less than 0.3% of the mother’s weight-adjusted dose. Thus, neonatal exposure to tacrolimus via breast milk is very low and does not represent a health risk to the breastfeeding infant.

Tacrolimus has a half-life of 4–57 hours. The dermal administration of tacrolimus is not problematic because little is absorbed and only low serum concentrations are achieved. The same is true for pimecrolimus , which is well tolerated by children from 3 to 23 months ( ).

There are no data on sirolimus and everolimus during breastfeeding.