Quantifying breast milk intake by term and preterm infants for input into paediatric physiologically based pharmacokinetic models

Abstract

Despite the many benefits of breast milk, mothers taking medication are often uncertain about the risks of drug exposure to their infants and decide not to breastfeed. Physiologically based pharmacokinetic models can contribute to drug‐in‐milk safety assessments by predicting the infant exposure and subsequently, risk for toxic effects that would result from continuous breastfeeding. This review aimed to quantify breast milk intake feeding parameters in term and preterm infants using literature data for input into paediatric physiologically based pharmacokinetic models designed for drug‐in‐milk risk assessment. Ovid MEDLINE and Embase were searched up to July 2, 2019. Key study reference lists and grey literature were reviewed. Title, abstract and full text were screened in nonduplicate. Daily weight‐normalized human milk intake (WHMI) and feeding frequency by age were extracted. The review process retrieved 52 studies. A nonlinear regression equation was constructed to describe the WHMI of exclusively breastfed term infants from birth to 1 year of age. In all cases, preterm infants fed with similar feeding parameters to term infants on a weight‐normalized basis. Maximum WHMI was 152.6 ml/kg/day at 19.7 days, and weighted mean feeding frequency was 7.7 feeds/day. Existing methods for approximating breast milk intake were refined by using a comprehensive set of literature data to describe WHMI and feeding frequency. Milk feeding parameters were quantified for preterm infants, a vulnerable population at risk for high drug exposure and toxic effects. A high‐risk period of exposure at 2–4 weeks of age was identified and can inform future drug‐in‐milk risk assessments.

Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery

“…by considering breastfeeding frequency as covariate affecting breast tissue volume when parameterizing the model) and for further structural refinement with e.g. collated data on breastfeeding frequency and milk volume intake by the neonate as published recently [65] which may constitute a relevant clearance pathway for some drugs. Since drug concentrations in the breast milk can be easily obtained through non-invasive methods, such information could be used to further inform lactation in the model.…”

Acute Maternal Fasting or Fluid Abstention Does Not Significantly Affect the Macronutrient Composition of Human Milk: Clinical and Clinical Research Relevance

“…Based on this structured, focused search, we conclude that neither acute fasting nor fluid abstention clinical significantly affect the macronutrient composition (lactose, protein, fat, solids, triglycerides, cholesterol) of human milk, so that women can be reassured on this aspect when this topic is raised during consulting. Furthermore and relevant to PBPK model development programs, this also means that-as a parameter to be used in PBPK model efforts-it is reasonable to assume a similar macronutrient composition of human milk in the immediate postoperative setting during fasting and fluid abstention [5][6][7][8].…”

“…Its valuable to confirm or reject this assumption. As recently discussed by Yeung et al, PBPK models have the ability to provide in silico estimates of drug exposure given the proper parameterization with host physiology and drug properties [5]. In order to fully exploit the utility of PBPK models in quantifying drug uptake in breastfed neonates, an accurate measure of infant feeding parameters, volume and frequency of maternal milk intake are needed [6].…”

“…In order to fully exploit the utility of PBPK models in quantifying drug uptake in breastfed neonates, an accurate measure of infant feeding parameters, volume and frequency of maternal milk intake are needed [6]. Human milk composition is another of these needed parameters [5,6].…”

Maternal Fasting or Fluid Abstention Does Not Significantly Affect the Macronutrient Composition of Human Milk: Clinical and Clinical Research Relevance

“…Following discussions with different colleagues and anesthesia associations during the development of (perioperative) guidelines on lactation following sedation and clinical consulting with individual lactating women, we realized that we only had focused on drugs or compounds 'temporarily added' to the maternal diet, and not on the nutritional or fluid intake 'temporarily removed' from the maternal diet as these women are commonly requested to abstain from enteral nutritional intake, enteral fluid intake, sometimes even including water. We therefore felt that a given the proper parameterization with host physiology and drug properties [5]. In order to fully exploit the utility of PBPK models in quantifying drug uptake in breastfed neonates, an accurate measure of infant feeding parameters, volume and frequency of maternal milk intake are needed [6].…”