Obstetrics & Gynecology · Medical Literature
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.
Clinical relevance
What are the current reporting practices and methodological approaches in published physiologically based pharmacokinetic (PBPK) models used to predict drug excretion into human breastmilk and infant exposure, and where do critical knowledge and reporting gaps exist? __SNAPSHOT__ {"studyDesign":"Systematic review with structured descriptive and narrative analysis; a purpose-built 22-item data abstraction tool (LAC-PBPK) was developed to evaluate reporting completeness","setting":"Multi-database systematic literature search (3 online databases); studies published through March 2025","sampleSize":"26 published PBPK modeling studies encompassing 54 medications","population":"Published PBPK modeling studies evaluating drug excretion into human breastmilk and/or infant exposure via breastfeeding; no restriction on drug class or therapeutic area","intervention":"PBPK modeling approaches used to simulate maternal-to-infant drug transfer via breastmilk (including whole-body maternal models, mammary distribution sub-models, and infant exposure estimation)","comparator":"Not applicable (descriptive systematic review; no experimental comparator)","primaryOutcome":"Completeness and consistency of PBPK model reporting practices across 22 structured domains, as assessed by the Lactation PBPK Model Reporting Checklist (LAC-PBPK); secondary outcomes included characterization of modeling structures, assumptions, and identified knowledge gaps","followUp":"Not applicable (systematic review of published studies)","fundingSource":"Not reported in abstract"}
Key findings
Twenty-six published studies modeling 54 medications met inclusion criteria. Using the 22-item LAC-PBPK data abstraction tool, only 4 of the 22 reporting domains (18%) were consistently reported across all studies; these were: the drug modeled, choice of mammary distribution model, context/purpose of PBPK modeling, and the modeling platform. The remaining 82% of reporting domains had incomplete or absent documentation in at least one study. Structurally, the majority of studies (88.4%) implemented a whole-body PBPK model architecture. Approximately half (53%) assumed perfusion-rate-limited milk excretion — a significant modeling simplification. The review identified that deficient reporting in source clinical lactation studies and knowledge gaps in infant and mammary physiology were the primary drivers of these modeling assumptions. No quantitative effect sizes, confidence intervals, or p-values are applicable to this descriptive systematic review. NNT/NNH are not applicable.
Practice implications
This systematic review establishes that the current landscape of lactation PBPK modeling is marked by substantial heterogeneity and inadequate reporting transparency. While PBPK models offer a mechanistically grounded approach to estimating infant drug exposure when clinical lactation data are unavailable or ethically difficult to obtain, confidence in model outputs is directly contingent on intended use, data availability, and transparent reporting — none of which are currently standardized. The near-universal use of whole-body model structures and the widespread assumption of perfusion-rate-limited excretion reflect underlying knowledge gaps in mammary physiology and active drug transport mechanisms rather than methodologically validated choices. Findings apply broadly to drug regulatory review, pharmacovigilance, and clinical decision-making regarding medication use in lactating individuals, but no specific drug safety conclusions can be drawn from this study. Populations not adequately represented include those taking medications for neglected tropical diseases, rare diseases, or those from low- and middle-income country settings. The study does not establish whether existing PBPK predictions are accurate for any specific drug or population. This is a review of abstracts and published reports; full-text depth of reporting evaluation may carry inherent limitations. The absence of a standardized, binding reporting framework is the central actionable finding. Practice should not change based on this study alone, but it provides a compelling evidence base for development and adoption of the proposed LAC-PBPK reporting framework — particularly in regulatory submission contexts. __LIMITATIONS__ 1. Only 26 studies covering 54 medications were identified, reflecting a still-nascent field; conclusions about reporting norms are drawn from a small corpus. 2. The LAC-PBPK checklist is a novel, non-validated tool developed by the study authors, introducing potential criterion bias. 3. Descriptive and narrative analysis precludes quantitative synthesis or meta-analysis. 4. Heterogeneity in drug classes, modeling platforms (e.g., Simcyp vs. Open Systems Pharmacology), and clinical contexts limits cross-study comparability. 5. The systematic review captures what was reported, not necessarily what was done; underreporting may overestimate methodological deficiencies. 6. The widespread assumption of perfusion-rate-limited excretion may mask active transporter contributions, but the true magnitude of this error cannot be quantified from this review. 7. Generalizability to regulatory decision-making is implied but not directly tested. 8. Funding sources for the included primary studies were not systematically evaluated for industry sponsorship bias. 9. Only published literature was searched; grey literature, regulatory submissions, and unpublished models were excluded, potentially introducing publication bias. 10. Full-text access limitations across the included studies are not specified in the abstract. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This systematic review demonstrates that lactation PBPK modeling is widely inconsistent in reporting: only 18% of pre-specified reporting domains were documented in all 26 identified studies, and the majority of models rely on simplifying assumptions (perfusion-rate-limited excretion) that may not reflect actual mammary drug transport biology. A fit-for-purpose, standardized reporting framework — such as the proposed LAC-PBPK checklist — is urgently needed before these models can be reliably used to inform clinical or regulatory decisions about medication safety in breastfeeding. Until such standards are adopted and validated, clinicians and regulators should interpret lactation PBPK model outputs with caution, with explicit attention to model transparency, the assumptions underlying milk excretion estimates, and the quality of source clinical lactation data.