Clinical study design and modeling approaches to study secretion of drugs in human milk

Breastfeeding has a multitude of benefits for both the lactating mother and her infant. However, lactating women often require medications for chronic and acute medical conditions, which may pose a significant risk due to drug transfer to infants via breastfeeding. Although most drugs may pass into human milk via passive diffusion, this should rarely be a reason to completely stop breastfeeding. Drug secretion into human milk is an area of research with a paucity of data. Performing clinical studies in lactating women is essential for understanding infant drug safety. However, it is practically challenging to enroll lactating women in these studies solely for the purpose of quantifying drug transfer into human milk. In the absence of clinical studies, non-clinical models-including in vitro, in vivo (animal studies), and in silico (predictive modeling tools)-can provide valuable insight into drug secretion into human milk. The objectives of this review are to summarize existing pharmacokinetic metrics to quantify drug transfer to human milk and elaborate upon clinical study designs in lactation. Furthermore, we aim to explore the utility of non-clinical models to quantify drug transfer into human milk, given the absence of clinical data. Finally, we discuss in silico models, including empirical equations used to derive milk-to-plasma ratios, as well as pharmacokinetic models to predict and analyze drug concentration-time profiles during lactation.