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

项目摘要 目前美国阿片类药物的流行包括越来越多的孕妇和产后与 阿片使用障碍(OUD)。治疗是孕产期和产后妇女的护理标准 用药治疗OUD(Moud)，特别是美沙酮或丁丙诺啡(SL BUP)。但是，在 近年来，出现了新的治疗OUD的选择，这些选择还没有在孕妇和 产后妇女。具体地说，使用阿片类拮抗剂纳曲酮(NTX)可能有利于 孕妇服用OUD，因为它避免了胎儿接触阿片类药物，并消除了新生儿使用阿片类药物的风险 戒断综合征(NOWS)。初步研究表明对怀孕和胎儿的影响很小 与NTX接触的结果，然而，总体上缺乏全面评估安全性的预期人类数据， 药效，以及各种结果。此外，药物动力学、药物基因组学、母乳 NTX在怀孕和产后使用时的转移和安全性尚不清楚。我们的父母 一项多中心前瞻性研究对50名服用NTX的孕妇和50名服用SL BUP的孕妇进行了检查 具有以下4个具体目标的比较队列研究：1)NTX与SL BUP的安全性和有效性： 在整个怀孕期间对母婴进行跟踪检查，直到产后12个月。 结局、胎儿结局和婴儿结局。2)NTX的药代动力学：NTX在体内的药代动力学 孕妇和产后妇女接受检查。3)药物基因组学和表观遗传修饰：我们检查 基因多态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。我们将测量哺乳妇女的母乳浓度 NTX以及母婴同时的血浆浓度。最近，扩展版 丁丙诺啡(SC BUP)的皮下制剂已经开发出来，通常用于非 怀孕的人。这些长效的BUP配方允许更个体化的治疗和 可以提高依从性和治疗保留率。在临床实践中，更多的提供者已经转向使用 产后SC BUP，但没有关于孕妇、产后或哺乳期妇女SC BUP的研究 已经进行了。作为行政补充的一部分，我们增加了以下两个目标：1) SC BUP在哺乳期妇女及其婴儿中的药代动力学：我们将招募10名产后妇女 对正在哺乳的SC BUP进行药代动力学和母乳水平的测定。2)安全性和有效性 产后母乳喂养妇女及其婴儿的SC BUP：我们将跟踪观察到12个月 产后检查母婴结局。这项研究的结果有望指导计划的 在最佳实践的背景下审查NTX和其他激动剂药物的使用的未来研究 妊娠期和产后期胎儿窘迫的治疗，以提高母婴的远期 结果。

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.