Title : Physiologically based pharmacokinetic model to predict lofexidine level during lactation
Abstract:
Lofexidine (LUCEMYRA®) is currently the only FDA-approved treatment for opioid withdrawal that is both non-opioid and non-addictive, making it especially important for use in pregnant and postpartum women amid the opioid crisis. However, limited information exists regarding its transfer into breast milk. This study seeks to address that gap by combining three complementary models: (1) a microfluidic blood-milk barrier chip, (2) a static transwell system using human mammary epithelial cells, and (3) a physiologically based pharmacokinetic (PBPK) lactation model. These tools aim to predict lofexidine secretion into breast milk and support safe treatment strategies for both mothers and infants.
A novel mammary epithelium-on-a-chip system was created using microfluidics, and a static transwell model was constructed using a non-cancerous human mammary epithelial cell line capable of forming tight junctions. Both models were applied to assess lofexidine permeability across the mammary cell barrier. The unbound fraction of lofexidine in breast milk was measured via a Rapid Equilibrium Dialysis (RED) assay. Eleven methods were employed to estimate the milk-to-plasma (M/P) ratio, including a previously established in vitro to in vivo extrapolation (IVIVE) method and other established techniques. A whole-body PBPK model using the Simcyp® v22 platform was also developed to simulate the time-course of lofexidine concentrations in plasma and breast milk.
A subline of MCF10A human mammary epithelial cells (MCF10A-TJ) was identified and cultured under optimized conditions to achieve trans-epithelial electrical resistance (TEER) values exceeding 1000 ?·cm², indicating tight barrier formation. The chip-based model exhibited slightly higher permeability for lofexidine than the static transwell model. M/P ratio predictions varied from 0.40 to 15.88; four approaches yielded values below 1, while seven produced estimates above 1—primarily in the range of 1.35 to 5.48. The PBPK model predicted an M/P ratio of around 2.0, consistent with the mid-range of these estimates.
Together, these integrated experimental and computational approaches offer a comprehensive framework for predicting lofexidine transfer into breast milk. The findings suggest a tendency for higher concentrations in milk than in plasma, highlighting potential safety implications. Further clinical pharmacokinetic studies in lactating women are warranted to confirm these predictions.
