Sirolimus excretion in breast milk: a preliminary investigation.

Background: Sirolimus is a mammalian target of rapamycin inhibitor that has been used in solid organ transplantation and is now increasingly being administrated to treat various manifestations of Tuberous Sclerosis (TSC). Lack of data regarding its safety during breastfeeding has led to its contraindication by pediatric and breastfeeding guidelines. Methods: Levels of sirolimus were evaluated in breast milk samples collected during 24 h on the 10th and 15th day postpartum, by a lactating TSC patient chronically medicated with 4 mg of sirolimus per day. Controls were healthy lactating women. Serum levels of sirolimus were also evaluated on the TSC patient on the 10th day postpartum (at the beginning of breast milk collection) but not in the newborn, since the patient was advised not to breastfeed. An ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method, including solid-liquid extraction (SLE) for sample preparation, was optimized and validated for the quantitation of sirolimus in breast milk. Results: After optimization, the SLE-UHPLC-MS/MS method allowed the detection of 100 pg sirolimus per mL Conclusion: Considering the low oral availability (∼15%) of sirolimus and the concentration found in breast milk, sirolimus is expected to achieve serum concentrations in the newborn below minimum therapeutic concentrations. The assessment of drug exposure in neonatal serum was not possible, as breastfeeding was not recommended. Thus, more studies are needed to characterize infant serum sirolimus concentrations and confirm its safety. Nevertheless, this research provides valuable information for breastfeeding counseling and respective guidelines, especially in patients with an increased risk of prematurity, in whom breast milk benefits are even more important.