Pragmatic and Contextualized Methods Selection for Safety Assessment of Infant Systemic Exposure Through Human Milk: The Milk4baby Decision Tree Approach A contribution from the concePTION Project

Anaëlle Monfort^1*Julia Macente²Martje Van Neste³Miao-Chan Huang²Nina Nauwelaerts²Getahun Befirdu Abza²Ursula Winterfeld⁴Anne Smits^5,6,7Karel Allegaert^3,5,6,8Pieter Annaert^2,9Monia Guidi^10,11,12Alice Panchaud^1,13*

• ¹Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, Geneva, Switzerland
• ²Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
• ³Laboratory of clinical pharmacology and pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
• ⁴Swiss Teratogen Information Service, Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Geneva, Switzerland
• ⁵Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Flemish Brabant, Belgium
• ⁶Child and Youth Institute, KU Leuven, Leuven, Belgium
• ⁷Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
• ⁸Department of Pharmacy, Erasmus Medical Center, Rotterdam, Netherlands
• ⁹BioNotus, Niel, Belgium
• ¹⁰Center for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne, Lausanne, Geneva, Switzerland
• ¹¹Institute of pharmaceutical Sciences of Western Switzerland, University of Geneva and University of Lausanne, Lausanne and Geneva, Switzerland
• ¹²Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Geneva, Switzerland
• ¹³Institute of Primary Health Care (BIHAM), University of Bern, Bern, Bern, Switzerland

More than 50% of women take at least one medication during lactation. However, 54% of drugs in the LactMed database lack lactation safety data, and only 2% have robust evidence. This highlights a significant gap in guidance for designing pharmacokinetic and safety studies characterizing infant safety following medication exposure during lactation, despite FDA guidelines recommending clinical lactation studies. Additional guidance is needed to select the most suitable study design for these studies. To address this, we identified key medication-related characteristics essential for designing lactation studies that assess infant safety following systemic exposure during lactation. This allowed us to develop a decision tree, named Milk4baby, to guide researchers in selecting the most appropriate methodological approach for each medication.Milk4baby was designed by reviewing the literature and iterative discussions with an interdisciplinary panel of experts in clinical pharmacology, lactation, and pharmacometrics on factors influencing the selection of the methodological approach and design of a lactation study. The decision tree first considers the prevalence of medication utilization in women of childbearing age. Next, the medication's safety profile in infants aged 0 to 2 years must be assessed using available safety data from infants, adults, and/or animals. Finally, the expected infant systemic exposure level is evaluated based on medication's oral bioavailability, transfer into human milk, risk of accumulation, and utilization patterns. After completing these steps, the decision tree recommends the most suitable methodological approach including case reports/case studies, population pharmacokinetic (popPK) modeling, physiologically based pharmacokinetic (PBPK) modeling and simulations, or pharmacoepidemiologic studies. Verification of the decision tree on 50 randomly selected medications from the LactMed and Le CRAT databases revealed that PBPK and case reports were the most appropriate approaches in 29 cases, primarily due to low prevalence of medication utilization.Designing popPK, PBPK, or pharmacoepidemiologic studies can be time-consuming and resourceintensive, while poorly designed case reports/case studies may yield limited or misleading information.Therefore, Milk4baby aims to help researchers enhance the efficiency and accuracy of determining infant safety following systemic exposure during lactation by choosing the most suitable strategy for lactation studies, ultimately supporting better-informed decisions for lactating women and their healthcare providers.