A Systematic Review of Published Physiologically Based Pharmacokinetic Models for Drug Excretion Into Human Breastmilk: Knowledge Gaps and Opportunities to Optimize Reporting and Modeling Practices.

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is increasingly used to predict infant exposure to medications via breast milk. Existing guidance on reporting of PBPK modeling analyses is unstructured and nonbinding to researchers. We evaluated reporting practices and modeling approaches in published PBPK modeling studies. A systematic search was conducted across three online databases. Studies published through March 2025 that leveraged PBPK to evaluate milk drug excretion and infant exposure were included. We developed a 22-item structured data abstraction tool-Lactation PBPK Model Reporting Checklist (LAC-PBPK). Study findings were reported using descriptive and narrative analyses. Twenty-six published studies modeling 54 medications met the inclusion criteria. Using the data abstraction tool, only 4 (18%) of reporting domains were reported in all studies. These include the drug modeled, choice of mammary distribution model, context of PBPK modeling (model purpose), and the modeling platform. Most studies (88.4%) implemented whole-body PBPK model structure, with one-half (53%) assuming perfusion-rate-limited milk excretion. Assumptions reflect modeling limitations, primarily due to inadequate reporting in clinical lactation studies and knowledge gaps in infant and mammary physiology. PBPK models can support mechanistic assessment of drug excretion into breast milk, but confidence in model outputs depends on intended use, data availability, and transparent reporting. This highlights the need for a prioritized, fit-for-purpose lactation PBPK reporting framework. From a regulatory perspective, transparent reporting and cautious selection of approaches for estimating infant milk intake, model performance evaluation, physiological extrapolation, and parameter uncertainty analyses are essential to ensure reproducibility and confidence in PBPK-informed infant exposure assessment.