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

Abstract

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 breastfeedingrelevant 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 ≈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.

Supplementing clinical lactation studies with PBPK modeling to inform drug therapy in lactating mothers: Prediction of primaquine exposure as a case example

“…The approach described here demonstrates how PBPK modeling can be used to predict drug exposures in both nursing mothers and infants while accounting for complex factors, such as time varying physiology 12,13,28 . Although it is accepted that this is an emerging area of interest with significant clinical relevance, evaluation of such approaches is ongoing and the results are promising.…”

Challenges Related to Acquisition of Physiological Data for Physiologically Based Pharmacokinetic (PBPK) Models in Postpartum, Lactating Women and Breastfed Infants—A Contribution from the ConcePTION Project

“…Strong differences in breastfeeding frequency can be explained by biological and cultural perspectives, considering fewer feeding frequencies are described in studies in urban communities or developed countries, whereas higher frequencies are reported in studies in rural communities or in developing countries [14,37]. However, it is suggested that the feeding frequency has a minimal impact on medicine exposure in breastfed infants [38].…”