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

基于生理学的药代动力学方法确定妊娠和哺乳期间抗癫痫药物的药物暴露程度

基本信息

批准号：
10461805
负责人：
ANGELA K BIRNBAUM
金额：
$ 55.04万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2027-05-31
项目状态：
未结题

项目摘要

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.

抽象的抗癫痫药物是最常用的致畸药物之一。在患有以下疾病的孕妇中癫痫，通常需要继续抗癫痫药物和增加剂量来预防癫痫发作恶化，但需要平衡子宫内暴露对胎儿的风险，例如先天性癫痫畸形和不良的神经发育结果。此外，母乳喂养还引入了另一种婴儿接触药物的途径并可能影响儿童发育。虽然测量药物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，它更重要难以计算胎儿的总体暴露情况或确定儿童的全部暴露程度通过母乳喂养。基于生理学的药代动力学（PBPK）方法将用于推进精准医学方法可在组织水平上表征药物浓度-时间曲线，从而允许评估癫痫女性患者达到最佳药物暴露所需的目标剂量，考虑到考虑怀孕期间胎儿和母乳喂养婴儿的药物暴露。来自双方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 MONEAD 中使用先前收集的数据和现有样本的新测量方法，动物数据、体外研究和一个新的外部验证队列，在关键时间点采样（以前没有获得）以确定抗癫痫药物浓度变化的机制基础怀孕和哺乳期。然后可以将这些数据与其他临床研究中的结果数据结合起来在两个非常脆弱的时期扩大我们对妇女和儿童的药物反应和安全的了解，怀孕和哺乳期。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

美国食品和药物管理局对怀孕和哺乳期的上市后承诺和要求的描述。

DOI：
发表时间：
2023-12
期刊：
影响因子：
6.7
作者：
Avachat, Charul;Younis, Islam R;Birnbaum, Angela K
通讯作者：
Birnbaum, Angela K

Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.

预测妊娠期间拉莫三嗪浓度的经验剂量策略。

DOI：
发表时间：
2023-10
期刊：
影响因子：
4.1
作者：
Barry, Jessica M;French, Jacqueline A;Pennell, Page B;Karanam, Ashwin;Harden, Cynthia L;Birnbaum, Angela K
通讯作者：
Birnbaum, Angela K

Women of childbearing age: What antiseizure medications are they taking?

育龄妇女：她们正在服用哪些抗癫痫药物？