A novel physiologically based pharmacokinetic (pbpk) modeling approach to facilitate safer medications during lactation

The National Institute of Child Health and Human Development awarded a $448,182 Project Grant to The Research Foundation For The State University Of New York (SUNY at Binghamton) under the Child Health and Human Development Extramural Research program (CFDA 93.865) for a project period from September 1, 2025 through March 31, 2027. The award funds the development of a novel physiologically based pharmacokinetic (PBPK) modeling approach to improve prediction of medication transfer into breast milk, addressing a critical safety concern for lactating women. The research endeavors focus on creating a systemic and generalized in vitro to in vivo extrapolation (IVIVE) and PBPK modeling approach that integrates reliable in vitro assays with robust physiological modeling to predict drug transfer into breast milk with higher accuracy, ultimately enabling safer medication use and precision dosage regimens for nursing mothers.

The project incorporates mechanistic modeling incorporating breast cancer resistance protein (BCRP) transporter and other efflux drug transporters that play significant roles in drug secretion into breast milk. A sub-award of undisclosed value was issued to the Regents of The University of Michigan (awarded October 17, 2025) to conduct quantitative proteomics analysis of transporters in mammary epithelial cells and human mammary tissues, contributing specialized analytical services to support the overall research objectives of characterizing drug transport mechanisms relevant to lactation.

Abstract

Drug transfer into breast milk has consistently been a safety concern for medication use in breastfeeding women. Studies have shown that women use an average of three different medicines during lactation. Knowing how much of a drug is secreted into breast milk is critical for ensuring the safe use of medications for lactating mothers. Carrier-mediated transport plays a crucial role in drug transfer into human milk, particularly through efflux transporters that actively transport their substrates into breast milk. However, many challenges remain on obtaining accurate information of drug transfer into breast milk. Our research endeavors in this area have made significant progress, including the development of a new in vitro to in vivo extrapolation (ivive) approach to predict milk-to-plasma ratios (m/p), a human normal mammary epithelial cell-based permeability assay, and a mechanistic physiologically based pharmacokinetic (pbpk) modeling approach incorporating breast cancer resistance protein (bcrp) transporter to predict drug pharmacokinetics in the milk. These findings demonstrate that better prediction of milk-to-plasma (m/p) ratio needs a systemic approach that contains reliable in vitro assays to generate extrapolable drug parameters and a robust ivive approach like pbpk modeling that can integrate physiology and drug characteristic to run proactive predictions for general population and design precision dosage regimens for certain populations. Therefore, we hypothesize that a systemic and generalized ivive and pbpk modeling approach will highly improve prediction accuracy of drug transfer into breast milk. Since efflux drug transporters present on mammary epithelium have a significant role on drug transfer into breastmilk and there is a huge knowledge GAP of their role, two p-glycoprotein (p-GP) drug substrates (clarithromycin and digoxin), four bcrp drug substrates (bupropion, cimetidine, ciprofloxacin and nitrofurantoin), and three passive diffusion drugs (atenolol, metoprolol and tramadol) will be used as probe drugs for this project. We will develop a novel lactating-like mammary epithelium barrier from human induced pluripotent stem cells (hipscs) to determine drug transfer in vitro and determine the fraction unbound of drugs in the plasma and breast milk. We will isolate human mammary epithelial cells (hmecs) from human breast milk and stimulate mecs from human reduction mammoplasty to be lactocyte-like cells. These cells will be used for running a stable heavy isotope-labeled full-length protein internal standard (is)-based targeted proteomics assay to quantify the absolute drug transporter expression for ivivc. Finally, a mechanistic lactation pbpk models will be developed by incorporating in vitro parameters, scaling factors, physiological and drug parameters. This research will have a significant impact to support safer medication use during lactation and develop precision therapeutics during lactation.