Safety, Efficacy, Pharmacokinetics, and Pharmacogenomics of Extended-Release Naltrexone in Pregnant Women - Administrative Supplement

缓释纳曲酮在孕妇中的安全性、功效、药代动力学和药物基因组学 - 行政补充文件

• 批准号: 10620577
• 负责人: Elisha Wachman
• 金额: $ 12.05万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620577
• 关键词: Administrative Supplement; Adverse event; Age-Months; Agonist; Animals; Biological Assay; Blood; Boston; Breast Feeding; Buprenorphine; California; Caring; Clinic; Cohort Studies; Collection; DNA Methylation; Data; Development; Dose; Drug Kinetics; Enrollment; Epigenetic Process; Exposure to; FDA approved; Formulation; Future; Genetic Polymorphism; Goals; Growth; Human Milk; Individual; Infant; Infant Health; Infrastructure; Injectable; Injections; Kinetics; Knowledge; Laboratories; Lactation; Maternal Health; Measurement; Measures; Medical center; Methadone; Modification; Mothers; Mucous Membrane; Naltrexone; Neonatal Abstinence Syndrome; Opioid; Opioid Antagonist; Outcome; Overdose; Parents; Perinatal; Persons; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Outcome; Pregnant Women; Prospective Studies; Provider; Pyrrolidinones; Recovery; Risk; Safety; Sampling; Time; Toxic effect; Umbilical Cord Blood; Universities; Urine; Woman; absorption; base; clinical practice; cohort; comparative; experience; fetal; high risk; human data; improved; individualized medicine; infant outcome; maternal outcome; neonatal outcome; neurodevelopment; opioid epidemic; opioid use disorder; pregnant; prenatal exposure; prospective; routine care; side effect; standard of care; subcutaneous; success; treatment response; Administrative Supplement; Adverse event; Age-Months; Agonist; Animals; Biological Assay; Blood; Boston; Breast Feeding; Buprenorphine; California; Caring; Clinic; Cohort Studies; Collection; DNA Methylation; Data; Development; Dose; Drug Kinetics; Enrollment; Epigenetic Process; Exposure to; FDA approved; Formulation; Future; Genetic Polymorphism; Goals; Growth; Human Milk; Individual; Infant; Infant Health; Infrastructure; Injectable; Injections; Kinetics; Knowledge; Laboratories; Lactation; Maternal Health; Measurement; Measures; Medical center; Methadone; Modification; Mothers; Mucous Membrane; Naltrexone; Neonatal Abstinence Syndrome; Opioid; Opioid Antagonist; Outcome; Overdose; Parents; Perinatal; Persons; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Outcome; Pregnant Women; Prospective Studies; Provider; Pyrrolidinones; Recovery; Risk; Safety; Sampling; Time; Toxic effect; Umbilical Cord Blood; Universities; Urine; Woman; absorption; base; clinical practice; cohort; comparative; experience; fetal; high risk; human data; improved; individualized medicine; infant outcome; maternal outcome; neonatal outcome; neurodevelopment; opioid epidemic; opioid use disorder; pregnant; prenatal exposure; prospective; routine care; side effect; standard of care; subcutaneous; success; treatment response

PROJECT ABSTRACT The current US opioid epidemic includes a rising number of pregnant and postpartum women struggling with opioid use disorders (OUD). The standard of care for pregnant and postpartum women with OUD is treatment with medication for OUD (MOUD), specifically methadone or sublingual buprenorphine (SL BUP). However, in recent years, newer options for the treatment of OUD have emerged that have not been studied in pregnant and postpartum women. Specifically, the use of naltrexone (NTX), an opioid antagonist, could be advantageous in pregnant women with OUD as it avoids fetal exposure to opioids and eliminates the risk for neonatal opioid withdrawal syndrome (NOWS). Preliminary studies demonstrate minimal impact on pregnancy and fetal outcomes with NTX exposure, however there is an overall lack of prospective human data fully evaluating safety, efficacy, and the full range of outcomes. In addition, the pharmacokinetics, pharmacogenomics, breast milk transfer and safety of NTX when used during pregnancy and the postpartum period are unknown. Our parent study examined 50 pregnant women on NTX compared with 50 on SL BUP in a multi-centered prospective comparative cohort study with the following 4 specific aims: 1) Safety and efficacy of NTX versus SL BUP: Mother-infant dyads are followed throughout the pregnancy until 12 months postpartum to examine maternal outcomes, fetal outcomes, and infant outcomes. 2) Pharmacokinetics of NTX: The pharmacokinetics of NTX in pregnant and postpartum women is examined. 3) Pharmacogenomics and epigenetic modification: We examine the impact of genetic polymorphisms on treatment response, and the impact of maternal treatment on DNA methylation. 4) NTX breastfeeding safety. We will measure breast milk concentrations from lactating women on NTX along with simultaneous maternal and infant plasma concentrations. Recently, extended-release formulations of subcutaneous buprenorphine (SC BUP) have been developed and are commonly used in non- pregnant individuals. These long-acting formulations of BUP allow for more individualization of treatment and could improve compliance and treatment retention. In clinical practice, more providers have moved towards using SC BUP in the postpartum period, however no studies of SC BUP in pregnant, postpartum, or lactating women have been conducted. We have added the following two aims as part of an administrative supplement: 1) Pharmacokinetics of SC BUP in lactating women and their infants: We will enroll 10 postpartum women who are on SC BUP who are breastfeeding to determine pharmacokinetics and breastmilk levels. 2) Safety and efficacy of SC BUP in postpartum breastfeeding women and their infants: We will follow the dyads to 12 months postpartum to examine maternal and infant outcomes. The results of this study hold the promise to guide planned future studies examining the use of both NTX and other agonist medications in the context of best practice treatment for OUD in pregnancy and postpartum period in order to improve long-term maternal and infant outcomes.

项目摘要 目前的美国阿片类药物流行包括挣扎的孕妇和产后妇女数量增加 阿片类药物使用障碍（OUD）。怀孕和产后妇女的护理标准是治疗 使用OUD（MOUD）的药物，特别是美沙酮或舌下丁丙诺啡（SL BUP）。但是，在 近年来，出现了尚未在怀孕和 产后妇女。具体而言，阿片类拮抗剂Naltrexone（NTX）的使用可能是有利的 孕妇患有OUD，因为它避免了胎儿暴露于阿片类药物，并消除了新生儿阿片类药物的风险 戒断综合征（现在）。初步研究表明对怀孕和胎儿的影响最小 NTX暴露的结果，但是总体上缺乏预期的人数据完全评估安全性， 功效和完整的结果范围。此外，药代动力学，药物基因组学，母乳 怀孕期间和产后使用时使用NTX的转移和安全性未知。我们的父母 研究检查了NTX上的50名孕妇，而在多中心的SL BUP上进行了50名孕妇 比较队列研究具有以下4个特定目的：1）NTX与SL BUP的安全性和功效： 在整个怀孕期间遵循母亲二元组，直到产后12个月来检查母亲 结果，胎儿结果和婴儿结果。 2）NTX的药代动力学：NTX的药代动力学 检查孕妇和产后妇女。 3）药物基因组学和表观遗传修饰：我们检查 遗传多态性对治疗反应的影响以及母体治疗对DNA的影响 甲基化。 4）NTX母乳喂养安全。我们将根据哺乳期妇女的母乳浓度 NTX以及同时的母体和婴儿血浆浓度。最近，扩展释放 已经开发了皮下丁丙诺啡（SC BUP）的配方，通常用于非 - 怀孕的人。这些bup的长效表述允许更多个性化的治疗和 可以改善合规性和保留率。在临床实践中，越来越多的提供商朝着使用 在产后时期SC BUP，但是在怀孕，产后或哺乳期妇女中没有对SC BUP的研究 已经进行了。我们添加了以下两个目标作为行政补充的一部分：1） SC BUP的药代动力学在泌乳妇女及其婴儿中：我们将注册10名产后妇女 在SC BUP上，他们正在母乳喂养，以确定药代动力学和母乳水平。 2）安全性和功效 产后母乳喂养妇女及其婴儿的SC BUP：我们将跟随二元组至12个月 产后检查母亲和婴儿的结局。这项研究的结果有望指导计划的 未来研究在最佳实践的背景下研究NTX和其他激动剂药物的使用 怀孕和产后的OUD治疗，以改善长期母亲和婴儿 结果。