Informing a Comprehensive Risk Assessment of Infant Drug Exposure From Human Milk: Application of a Physiologically Based Pharmacokinetic Lactation Model for Sotalol

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding-relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures approximate to 20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2-4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

Automated summary

Characterization of drug exposure in breastfeeding infants through human milk is important and not well-studied. This study used a physiologically based pharmacokinetic model to simulate the drug exposure of sotalol in infants. The simulations predicted the effects of various factors such as sex, body size, breastfeeding frequency, age, and maternal dose on the drug exposure during breastfeeding. The results showed minimal effects of sex and frequency on total sotalol exposure, but suggested that infants with higher height and weight percentiles have higher predicted exposures due to increased milk intake.