PBPK models for lactation studies

Many breastfeeding mothers need pharmacotherapy. However, guidance about the exposure-related safety for breastfed infants is missing for most medicines. ConcePTION has developed a non-clinical framework for lactation studies. The framework is based on three pillars to support evidence-based guidance and includes physiologically-based pharmacokinetic, or PBPK models. These computer models offer the possibility to predict the pharmacokinetic profile of medicines in human milk, and subsequent systemic exposure to the breastfed infant, even when clinical data are lacking.

The ConcePTION project has developed a generic workflow to establish PBPK models for lactation using the open-source software PK-Sim/MoBi v9.1 (Open Systems Pharmacology) and the commercial software SimCYP (Certara). Initially, the PBPK models were developed relying on a semi-mechanistic approach, resulting in reasonable predictions of the human milk concentrations for 80 % of the evaluated medicines. Ongoing efforts aim to establish fully mechanistic PBPK models via integration of the in vitro data generated in cultured hMECs. The ConcePTION PBPK model predictions can help to prioritize clinical studies for lactation, and support safety-assessment of maternal medicines during lactation.

In addition to the in silico PBPK models, the ConcePTION non-clinical framework for lactation studies includes in vitro models and in vivo models. The project has also developed a framework for clinical lactation studies.

Publications

Van Neste M, Bogaerts A, Nauwelaerts N, Macente J, Smits A, Annaert P, Allegaert K. Challenges Related to Acquisition of Physiological Data for Physiologically Based Pharmacokinetic (PBPK) Models in Postpartum, Lactating Women and Breastfed Infants-A Contribution from the ConcePTION Project. Pharmaceutics. 2023 Nov 12;15(11):2618. doi: 10.3390/pharmaceutics15112618. PMID: 38004596; PMCID: PMC10674226.

Nauwelaerts N, Macente J, Deferm N, Bonan RH, Huang MC, Van Neste M, Bibi D, Badee J, Martins FS, Smits A, Allegaert K, Bouillon T, Annaert P. Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling-A Contribution from the ConcePTION Project. Pharmaceutics. 2023 May 11;15(5):1469. doi: 10.3390/pharmaceutics15051469. PMID: 37242712; PMCID: PMC10223637.

Cardoso E, Guidi M, Nauwelaerts N, Nordeng H, Teil M, Allegaert K, Smits A, Gandia P, Edginton A, Ito S, Annaert P, Panchaud A. Safety of medicines during breastfeeding – from case report to modeling: a contribution from the ConcePTION project. Expert Opin Drug Metab Toxicol. 2023 Jan-Jun;19(5):269-283. doi: 10.1080/17425255.2023.2221847. Epub 2023 Jun 13. PMID: 37269321.

Nauwelaerts N, Deferm N, Smits A, Bernardini C, Lammens B, Gandia P, Panchaud A, Nordeng H, Bacci ML, Forni M, Ventrella D, Van Calsteren K, DeLise A, Huys I, Bouisset-Leonard M, Allegaert K, Annaert P. A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project. Biomed Pharmacother. 2021 Apr;136:111038. doi: 10.1016/j.biopha.2020.111038. Epub 2021 Jan 30. PMID: 33526310.