Coupling Pre- and Postnatal Infant Exposures with Physiologically Based Pharmacokinetic Modeling to Predict...

Although breastfeeding ensures optimal infant development and maternal health, mothers taking medications may abandon breastfeeding because of uncertainties regarding toxicity to infants. Current methods in predicting infant risk to maternal medication exposure do not account for breastfeeding-related variability or in utero exposure via the umbilical cord (UC). Previously, our workflow integrated variability in infant anatomy and physiology, breast milk intake volume, and drug concentrations in breast milk using physiologically based pharmacokinetic (PBPK) modeling. The upper area under the curve ratio (UAR) was then calculated to assess infant risk from maternal drug. Herein, we enhanced this workflow by coupling pre- and postnatal exposures to predict the overall levetiracetam exposure in breastfeeding infants.

A published pediatric PBPK model of levetiracetam was used to simulate an infant population (n = 100). Daily infant doses were simulated using a weight-normalized milk intake model to calculate volumes ingested across age groups, alongside literature-derived or simulated milk concentrations across maternal doses to predict infant concentrations. Published UC concentrations were used to develop a cord-coupled neonatal model (CCM), which was integrated with the PBPK and milk intake models and evaluated by comparing observed and simulated infant blood concentrations using a 90% prediction interval (PI).

UC concentration data from 14 mothers were used to develop the CCM. A total of 16 paired (known milk concentrations) and two unpaired (unknown milk concentrations) individual infant concentrations were identified for evaluating the model along with population values of 64 infants from two age groups (2-4 and 7-31 days). The CCM improved the predictions overall compared with the original workflow, largely due to improvements for the youngest age group evaluated. Overall, 83% (10 of 12) of the individual infant plasma concentrations were successfully captured within the 90% PI for the paired, quantifiable (i.e. above the limit of quantification) evaluation datasets. After administration of a maternal dose of levetiracetam 2000 mg, the calculated UAR ranged from 0.13 to 0.27 for the 95th percentile infants.

To our knowledge, this is the first report to combine prenatal levetiracetam exposures from the UC and postnatal exposures from breastfeeding to predict overall infant drug exposure. The results indicate that infant exposure in infants aged 0-7 days may approach therapeutic levels of levetiracetam in the highest-risk infants (i.e. 95th percentile), with a low likelihood of adverse effects based on published clinical studies. This integrated modeling approach provides a more holistic analysis of neonatal exposures. It can be applied in future studies to derive the UAR of drugs administered during breastfeeding to identify infants at risk of potential toxicity.