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Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CL H ) and renal clearance (CL R ). The typical value of the total clearance (CL, the sum of CL R and CL H ) was 3.09 ml/h and expressed as CL/WT median = 3.96 ml/h/kg, where WT median is the median body weight. The intersubject variability of CL R and CL H were 61% and 207%, respectively. The typical value of the volume of distribution V p = 366 ml (V p /WT median = 470 ml/kg), and its intersubject variability was 38.8%.Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?With current weight-based dosing, indomethacin exposure is variable, and clinical response is unpredictable in preterm infants.

Human milk is essential for infant nutrition and immunity, providing protection against infections and other immune-mediated diseases during the lactation period and beyond in later childhood. Milk contains a broad range of bioactive factors such as nutrients, hormones, enzymes, immunoglobulins, growth factors, cytokines, and antimicrobial factors, as well as heterogeneous populations of maternal cells. The soluble and cellular components of milk are dynamic over time to meet the needs of the growing infant. In this study, we utilize systems-approaches to define and characterize 62 analytes of the soluble component, including immunoglobulin isotypes, as well as the cellular component of human milk during the first two weeks postpartum from 36 mothers. We identify soluble immune and growth factors that are dynamic over time and could be utilized to classify milk into different phenotypic groups. We identify 24 distinct populations of both epithelial and immune cells by single-cell transcriptome analysis of 128,016 human milk cells. We found that macrophage populations have shifting inflammatory profiles during the first two weeks of lactation. This analysis provides key insights into the soluble and cellular components of human milk and serves as a substantial resource for future studies of human milk.

Breast milk (BM) is a complex fluid containing factors essential for infant nutrition and immunity. Breastfeeding has been shown to be protective against infections and other immune-mediated diseases during the lactation period and beyond in later childhood. This suggests that BM also imprints the neonatal immune system and influences long-term health. BM also contains populations of maternal-derived cells. Which factors in BM that are important for neonatal health and how they change during lactation have not been well-defined. In this study, we used a single-cell transcriptomic approach to identify and define cell types of early and transitional milk. We collected BM samples from mothers of infants 2–5 days (early milk) and 8–12 days (transitional milk) after delivery. We applied single-cell RNA sequencing on over 154,000 BM-derived cells. We identified 25 transcriptionally distinct populations of cells in the BM. As expected, the most abundant cells in BM were mammary epithelial cells and macrophages. Monocytes, T cells, dendritic cells, and neutrophils were also present and had a higher frequency in week 2, suggesting that some immune cells may remain abundant in the early days of lactation and slowly decline as milk matures. We also detected a small number of stem and progenitor, natural killer and B cells in the BM at a higher frequency in week 1. This work provides an atlas of the cellular component in human milk at two timepoints of lactation. In addition to cell identity and frequencies, we have also uncovered unique molecular pathways that are activated in BM cells. This work will lay the foundation for future studies of how these cells influence neonatal health. Supported by funding from Children's Mercy Kansas City