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

摘要 抗癫痫药物是最常见的处方致畸药物之一。在怀孕的妇女中 癫痫、继续服用抗癫痫药物和增加剂量往往是必要的，以防止 癫痫发作恶化，但需要平衡胎儿在宫内暴露的风险，如先天性 畸形和不良的神经发育结果。此外，母乳喂养还会带来另一种 这可能是婴儿接触药物的途径，并可能影响儿童的发育。虽然药物的计量 血浆中的浓度被认为反映了母亲体内作用部位的药物浓度，它比 很难解释对胎儿的总体接触或确定对儿童的全面接触程度 通过母乳喂养。基于生理的药代动力学(PBPK)方法将用于促进 精确医学方法在组织水平上表征药物浓度-时间分布 评估癫痫女性患者达到最佳药物暴露所需的目标剂量，考虑到 考虑到怀孕期间胎儿和哺乳婴儿接触药物的情况。来自两家公司的信息 基础科学和临床研究将用于开发、评估和验证PBPK模型。这笔赠款将 在临床研究中使用先前收集的数据和现有样本的新措施 数据、体外研究和新的外部验证队列，在关键时间点(而不是以前)采样 获得)以确定抗癫痫药物浓度变化的机制基础 怀孕和哺乳。然后，这些数据可以与其他临床研究中的结果数据相结合 在两个非常脆弱的时期扩大我们对妇女和儿童药物反应和安全性的知识， 怀孕和哺乳。

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.