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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10461805
• 关键词: Affect; Animal Model; Animals; Antiepileptic Agents; Basic Science; Blood flow; Breast Feeding; Breastfed infant; Child; Child Development; Clinical; Clinical Data; Clinical Research; Cognitive; Cohort Studies; Congenital Abnormality; Data; Data Set; Development; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Enzymes; Epilepsy; Evaluation; Exposure to; Fetal Tissues; Fetus; First Pregnancy Trimester; Glucuronides; Glucuronosyltransferase; Goals; Grant; Human Milk; In Vitro; Individual; Infant; Kidney; Knowledge; Lactation; Late pregnancy; Levetiracetam; Measurement; Measures; Methods; Modeling; Mothers; Organ; Outcome; Partition Coefficient; Pharmaceutical Preparations; Physiological; Plasma; Population; Postpartum Period; Pregnancy; Pregnant Women; Renal clearance function; Risk; Route; Safety; Sampling; Seizures; Site; Teratogens; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Up-Regulation; Validation; Visit; Woman; animal data; autism spectrum disorder; base; clinical care; cohort; drug clearance; drug exposure in utero; early pregnancy; fetal; lamotrigine; liver metabolism; neurodevelopmental effect; pharmacokinetic model; precision medicine; predictive modeling; pregnant; prenatal exposure; prevent; prospective; response; side effect; simulation; study population; tool

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.

摘要

项目成果

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？

• DOI: 10.1111/bcp.15555
• 发表时间: 2023
• 期刊: British journal of clinical pharmacology
• 影响因子: 3.4
• 作者: Avachat,Charul;Birnbaum,AngelaK
• 通讯作者: Birnbaum,AngelaK

Management of Anti-Seizure Medications during Pregnancy: Advancements in The Past Decade.

怀孕期间抗塞氏菌药物的管理：过去十年的进步。

• DOI: 10.3390/pharmaceutics14122733
• 发表时间: 2022-12-06
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Avachat, Charul;Barry, Jessica M.;Lyu, Xintian;Sherwin, Catherine M.;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: 10.1002/phar.2856
• 发表时间: 2023
• 期刊: Pharmacotherapy
• 影响因子: 4.1
• 作者: Barry,JessicaM;French,JacquelineA;Pennell,PageB;Karanam,Ashwin;Harden,CynthiaL;Birnbaum,AngelaK
• 通讯作者: Birnbaum,AngelaK

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: 10.1002/cpt.3059
• 发表时间: 2023
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Avachat,Charul;Younis,IslamR;Birnbaum,AngelaK
• 通讯作者: Birnbaum,AngelaK