Senior Scientist, Clinical & Quantitative Pharmacology Vertex Pharmaceuticals Incorporated, Massachusetts, United States
Disclosure(s):
Sharmistha Das: No financial relationships to disclose
Objectives: Based on data compiled in the publicly-available LactMed database, breastfeeding mothers taking CYP3A inhibitors or inducers (ritonavir, itraconazole, efavirenz, and rifampin) expose their infants to these drugs at subtherapeutic levels. Whether these subtherapeutic exposures can cause significant drug-drug interactions (DDIs) if the infants are administered CYP3A substrates is not known. The aim of this analysis is to evaluate the DDI potential in infants between CYP3A inhibitors or inducers administered through breastmilk and the established CYP3A probe substrate midazolam using a combination of information about medication concentrations from LactMed with physiologically based pharmacokinetic (PBPK) simulations. These results can be extrapolated to other sensitive CYP3A substrates administered to infants.
Methods: PBPK modeling was performed using Simcyp V23 to evaluate DDIs in a breastfed infant taking midazolam while the mother is administered CYP3A inducers or inhibitors. The reported concentrations of the CYP3A inducers efavirenz [1,2] and rifampicin [3,4] and the CYP3A inhibitors itraconazole [5,6] and ritonavir [7,8] in breastmilk were extracted from the LactMed database. The drug concentrations were used to calculate the total dose of these medications administered to the infant in breastmilk consumed daily by an exclusively breastfed 6-month-old infant according to the FDA guidelines [9], assuming dosing 8 times a day. Using Simcyp’s pediatric population model, a fixed individual trial was designed to specifically simulate 6-month-old infants [10]. The PBPK simulations for these infants were performed to evaluate the pharmacokinetics of midazolam in the presence and absence of these medications. Results were summarized for changes in the area under the curve (AUC) and maximum concentration (Cmax) of midazolam.
Results: The PBPK simulations of the PK for these medications in breast-fed infants were consistent with the values reported in the LactMed database. Additionally, the PBPK simulations demonstrated varying degrees of DDIs between midazolam and maternal medications in a breastfed infant. Changes in midazolam exposure in the infant when the mother was taking CYP3A inducers or inhibitors ranged from having a moderate effect to not having a clinically relevant effect.
Conclusions: Overall, the findings suggest that even though breastfed infants are exposed to sub-therapeutic levels of the considered CYP3A inhibitors and inducers, those exposures are sufficient to introduce DDIs if the infants are taking sensitive CYP3A substrates. These results highlight the importance of considering maternal drug use when evaluating pharmacokinetic changes in drugs directly administered to breastfed infants.
Citations: [1] National Center for Biotechnology Information. (2018). Drug metabolism. National Library of Medicine. Retrieved March 1st 2025, from https://www.ncbi.nlm.nih.gov/books/NBK501534/ [2] Oumar AA, Bagayoko-Maiga K, Bahachimi A, et al. Efavirenz and lopinavir levels in HIV-infected women and their nursing infants, in Mali. J Pharmacol Exp Ther 2018;366:479-84. [3] National Center for Biotechnology Information. (2018). Drug metabolism. National Library of Medicine. Retrieved March 1st 2025, from https://www.ncbi.nlm.nih.gov/books/NBK501348/ [4] Kawuma A, Ojara F, Buzibye A, et al. Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs. CPT Pharmacometrics Syst Pharmacol 2024;13:1915-23. [5] National Center for Biotechnology Information. (2018). Drug metabolism. National Library of Medicine. Retrieved March 1st 2025, from https://www.ncbi.nlm.nih.gov/books/NBK501541/ [6] Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther 2012;17:1511-9 [7] National Center for Biotechnology Information. (2018). Drug metabolism. National Library of Medicine. Retrieved March 1st 2025, from https://www.ncbi.nlm.nih.gov/books/NBK500573/ [8] Briggs GG, Freeman RK, Towers CV, et al. Drugs in pregnancy and lactation, 11th ed. Baltimore. Williams & Wilkins. 2017. [9] U.S. Food and Drug Administration. (2002). Clinical lactation studies: Considerations for study design. Retrieved March 1st, 2025, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-lactation-studies-considerations-study-design [10] World Health Organization. (n.d.). Weight-for-age. World Health Organization. Retrieved March 1st, 2025, from https://www.who.int/tools/child-growth-standards/standards/weight-for-age
Keywords: drug-drug interaction, pediatric, lactation and breastfeeding
