Background
Physiologically Based pharmacokinetic (PBPK) modeling is increasingly being used to optimize pharmacotherapy in understudied and complex patient populations (1). Several non-binding guidelines have been published by regulatory bodies and consortia (3–6), however, there is no standardized checklist to guide reporting of PBPK modeling-related results and information. The present review aimed to evaluate reporting current practices and identify opportunities to optimize future PBPK modeling efforts.
Methods
A systematic search was conducted in three online sources (SCOPUS, PubMed, Google scholar) using the terms “postpartum”, ”Breastfeeding”, “Physiologically Based Pharmacokinetic”, “PBPK”, “drug concentration”. We included studies reporting PBPK modeling approach evaluating plasma-to-breast milk transfer and infant exposure to human pharmaceuticals, and published until May 2025. Study articles based on conference abstracts and those with inaccessible full text materials were excluded. A data abstraction tool was developed following existing regulatory and consortia guidelines, under the guidance of PBPK modeling experts and academic supervisors. Two reviewers abstracted and reviewed the retrieved information. Descriptive and narrative analysis were used to summarize the overall reporting practices and PBPK modeling approaches.
Results
A total of twenty six articles met the search and screening criteria. Whereas majority of studies were adopted full-PBPK model types (88.4%) with perfusion-rate limited drug transfer (53%), at least 61% of studies did not explicitly report sources of model data. However, less than half of the studies reported information on breast milk PH, fat content, infant gestational age, free drug in skimmed milk, and mammary transporter involvement in the drug plasma-to-breast-milk transfer. Among the 58 drugs modeled, majority were antimicrobial agents (47%) and CNS drugs (29%). Overall, model parameterization data were majorly derived from in-vitro (57.7%), Clinical sources (53.8%), and assumed values (34.6%), especially for drug metabolism and clearance. Majority of model assumptions (70%) were focused on maternal, mammary, and infant physiology.
Conclusion
The findings demonstrate inconsistencies in reporting of PBPK model development information. Therefore, there is need to harmonize reporting and approaches in lactation PBPK modeling.
References
1. Rowland Yeo K, Gil Bergland E, Chen Y. Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future. Clinical Pharmacology & Therapeutics.
2. Dubbelboer IR, Le Roux-Pullen L, Gehring R. Systematic review of physiologically based kinetic lactation models for transfer of xenobiotic compounds to milk. Toxicology and Applied Pharmacology [Internet]. 2023 May 15 [cited 2024 Nov 11];467:116495. Available from: https://www.sciencedirect.com/science/article/pii/S0041008X23001333
3. EMA. Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation [Internet]. European Medicines Agency; 2019 [cited 2025 Feb 21]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-and-simulation_en.pdf
4. U. S. FDA. Physiologically Based Pharmacokinetic Analyses – Format and Content: Guidance for Industry. 2024.
5. Shebley M, Sandhu P, Emami Riedmaier A, Jamei M, Narayanan R, Patel A, et al. Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective. Clinical Pharmacology & Therapeutics [Internet]. 2018 [cited 2024 Sep 12];104(1):88–110. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1013
6. Tan YM, Chan M, Chukwudebe A, Domoradzki J, Fisher J, Hack CE, et al. PBPK model reporting template for chemical risk assessment applications. Regul Toxicol Pharmacol [Internet]. 2020 Aug [cited 2025 Feb 21];115:104691. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188465/
