Physiological-based Pharmacokinetics Approach to Determine the Extent of Drug Exposure of Antiseizure Medications During Pregnancy and Breastfeeding

ABSTRACT Antiseizure medications are one of the most commonly prescribed teratogens. In pregnant women with epilepsy, continuation of antiseizure medications and dose increases are often necessary to prevent seizure worsening, but need to be balanced against the fetal risks of in utero exposure, such as congenital malformations and adverse neurodevelopmental outcomes. Additionally, breastfeeding introduces another route of drug exposure to the infant and can affect child development. Although measurement of drug concentration in plasma is thought to reflect drug concentrations at the site of action in the mother, it is more difficult to translate the overall exposure to the fetus or determine the full extent of the exposure to the child through breastfeeding. Physiological-based pharmacokinetic (PBPK) methods will be used to advance a precision medicine approach to characterize drug concentration-time profiles at the tissue level allowing evaluation of target doses needed to achieve optimal drug exposure in women with epilepsy, taking into account drug exposure to the fetus during pregnancy and to the breastfeeding infant. Information from both basic science and clinical studies will be used to develop, evaluate, and validate PBPK models. This grant will use previously collected data and new measures from existing samples in the clinical study MONEAD, animal data, in vitro studies, and a new external validation cohort with sampling at critical timepoints (not previously obtained) to determine the mechanistic basis of alterations in antiseizure medication concentrations during pregnancy and lactation. These data can then be combined with outcome data in other clinical studies to expand our knowledge of drug response and safety in women and children during two very vulnerable times, pregnancy and lactation.