Low Transfer of Tacrolimus and Its Metabolites into Colostrum of Graft Recipient Mothers

Abstract

Currently, the majority of neonates born to organ recipient mothers on chronic immunosuppressive therapy are formula fed. However, over the past few years, evidence has grown, suggesting that breastfeeding might be possible and beneficial. We designed a study assessing the transfer of tacrolimus into the colostrum of posttransplant mothers. We assessed the amount of tacrolimus and its metabolites, M-1 and M-3, that would be ingested by the breastfed neonates. Concentrations of tacrolimus and its metabolites were measured in colostrum from 14 posttransplant mothers as well as in venous cord blood and venous blood of the neonates. Test material analysis was performed by liquid chromatography coupled with mass spectrometry (LC/MS). The amount of ingested formula was registered, which allowed for estimation of the amount of tacrolimus and its metabolites that would be ingested by breastfed infants. The mean amount of tacrolimus that would be ingested by the neonates in maternal milk was 151.4 ng/kg/24 h (standard deviation SD ± 74.39); metabolite M-1: 23.80 ng/kg/24 h (SD ± 14.53); and metabolite M-3: 13.25 ng/kg/24 h (SD ± 9.05). The peak level of tacrolimus and metabolite M-1 in colostrum was noted 8 h after an oral dose (3.219 ng/mL SD ± 2.22 and 0.56 ng/mL SD ± 0.60, respectively) and metabolite M-3 after 6 h (0.29 ng/mL SD ± 0.22). Low concentrations of tacrolimus and its metabolites, M-1 and M-3, in colostrum show that neonates will ingest trace amounts of the drug. Further studies are required to fully assess the safety of breastfeeding by posttransplant mothers.

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

“…62,64 Kociszewaska-Najman et al measured the concentrations of the Tac metabolites 13-O-demethyl tacrolimus (13-DMT) and 15-O-demethyl tacrolimus (15-DMT) in cord blood. 65 The mean concentration of Tac, 13-DMT, and 15-DMT in cord blood did not differ from that in fetal venous blood. Zheng et al 59 observed no difference in the primary Tac metabolite concentrations between the arterial and venous umbilical cord blood.…”

“…Tac concentrations in breast milk were reported to range between 0.0038 and 3.219 ng/ mL. 47,57,59,65,[115][116][117] Milk-to-whole-blood and milk-toplasma ratios were 0.08-0.23 115,116 and 0.12-0.5, 47,59,117 respectively. Zheng et al investigated Tac excretion into breast milk over a 12-hour steady-state dosing interval in one patient.…”

“…59 The estimated daily Tac ingestion by infants via breast milk ranged between 0.059% and 0.9% of the mother's weight-adjusted dose, assuming a daily intake of 150 mL of milk per kilogram. 47,57,59,65,[115][116][117] Based on the highest measured Tac concentration in breast milk (3.219 ng/mL 65 ) and the assumption that an infant consumes 150 mL/kg milk per day, the maximum ingested dose would be 0.00048 mg/kg per day, which is far lower than the lowest recommended intake for pediatric SOT recipients (0.15 mg/kg per day). 65 Kociszewska-Najman et al 65 Breastfed children were able to eliminate Tac to undetectable concentrations over time.…”

“…47,57,59,65,[115][116][117] Based on the highest measured Tac concentration in breast milk (3.219 ng/mL 65 ) and the assumption that an infant consumes 150 mL/kg milk per day, the maximum ingested dose would be 0.00048 mg/kg per day, which is far lower than the lowest recommended intake for pediatric SOT recipients (0.15 mg/kg per day). 65 Kociszewska-Najman et al 65 Breastfed children were able to eliminate Tac to undetectable concentrations over time. 47,57,117,118 Bramham et al observed a decline in Tac concentrations of approximately 15% per day in both breastfed and bottle-fed infants.…”

“…During breastfeeding, infants will ingest very low amounts of Tac, which are estimated to range between 0.059% and 0.9% of the mother's weight-adjusted daily dose. 65 No Tac-related adverse events have been reported in breastfed children, and thus, Tac treatment is considered not an absolute contraindication for breastfeeding. Moreover, TDM of the infant is unlikely to improve patient care.…”