Safety, pharmacokinetics and efficacy of extended-release naltrexone in pregnant women with opioid use disorder

项目摘要 妊娠期阿片类药物使用障碍(OID)是美国的公共健康危机；目前的治疗标准是治疗 使用阿片类激动剂，如丁丙诺啡(BPH)，显示可以改善妊娠结局 新生儿禁欲综合征(NAS)的相关风险和可能的长期神经发育 后果。阿片类拮抗剂纳曲酮是治疗妊娠期尿失禁的一种新方法 这不会使发育中的胎儿暴露于阿片类药物，大大降低了NAS的风险，并有可能 改善孕产妇和婴儿的结局。初步的动物和人体研究表明影响很小 关于纳曲酮暴露对妊娠和胎儿结局的影响，然而总体上缺乏前瞻性 全面评估安全性、有效性和母婴结局的人类数据。此外， 纳曲酮的药代动力学、药物基因组学、胎盘移植、母乳移植和安全性 在孕期和产后期使用的情况不详。我们建议通过以下方式来填补这些知识空白 孕妇应用纳曲酮的安全性、有效性、药代动力学和药物基因组学研究 对于ODS，在整个怀孕期间和第一年后评估综合母婴结局 出生。我们将招募50名孕前稳定的孕妇服用缓释纳曲酮(XR-NTX)。 来自波士顿医学中心和北卡罗来纳大学的50名接受BPH治疗的女性 多中心前瞻性比较队列研究。该项目的具体目标是：1)安全和 疗效：比较产妇结局(安全性、复发率、保留率)、胎儿结局(生长、胎儿 怀孕期间直到12个月后的婴儿结局(NAS、生长、神经发育) 2)药代动力学：测定XR-NTX在孕期和产后的药代动力学 3)基因组学：检查基因变异和表观遗传修饰之间的联系 XR-NTX治疗后MU-阿片受体(OPRM1)基因及全局DNA甲基化的变化 和BPH在母亲、胎盘和婴儿中；和4)母乳：测量母乳浓度 XR-NTX和相应的婴儿相对剂量，以确定对哺乳期妇女的安全性。我们假设 XR-NTX将被证明是孕妇和产后妇女的一种安全有效的治疗选择 与阿片类激动剂治疗相比，OUD的孕产妇和婴儿结局有所改善。这个 这项研究的结果有望指导计划中的未来研究，检查XR-NTX和 在最佳实践治疗的背景下的其他激动剂药物，以改善妊娠期OUD 孕产妇和婴儿的长期结局。

PROJECT ABSTRACT Opioid use disorders (OUDs) in pregnancy are a US public health crisis; current standard of care is treatment with an opioid agonist such as buprenorphine (BPH), shown to improve pregnancy outcomes however with an associated risk for neonatal abstinence syndrome (NAS) and possible long-term neurodevelopmental consequences. The opioid antagonist naltrexone represents a novel treatment option for OUD in pregnancy which would not expose the developing fetus to opioids, greatly reducing the risk for NAS and potentially improving maternal and infant outcomes. Preliminary animal and human studies demonstrate minimal impact on pregnancy and fetal outcomes with naltrexone exposure, however there is an overall lack of prospective human data fully evaluating safety, efficacy, and the full-range of maternal and infant outcomes. In addition, the pharmacokinetics, pharmacogenomics, placental transfer, breast milk transfer and safety of naltrexone when used during pregnancy and the postpartum period are unknown. We propose to fill these gaps in knowledge by studying the safety, efficacy, pharmacokinetics, and pharmacogenomics of naltrexone for pregnant women with OUDs, evaluating comprehensive mother-infant outcomes throughout the pregnancy and first year after birth. We will enroll 50 pregnant women stabilized pre-pregnancy on extended-release naltrexone (XR-NTX) and 50 comparison women on BPH from Boston Medical Center and the University of North Carolina in this multi-centered prospective comparative cohort study. The specific aims of this project are: 1) Safety and Efficacy: To compare maternal outcomes (safety, relapse, retention in care), fetal outcomes (growth, fetal distress), and infant outcomes (NAS, growth, neurodevelopment) during pregnancy until 12 months post- delivery; 2) Pharmacokinetics: To determine the pharmacokinetics of XR-NTX in pregnant and postpartum women; 3) Genomics: To examine the association between genetic variants and epigenetic modification in the mu-opioid receptor (OPRM1) gene, as well as global DNA methylation changes after treatment with XR-NTX and BPH within the mother, placenta, and infant; and 4) Breast milk: To measure breast milk concentrations of XR-NTX and corresponding infant relative dose to determine safety for lactating women. We hypothesize that XR-NTX will be demonstrated to be a safe and effective treatment option for pregnant and postpartum women with OUD, with improved maternal and infant outcomes in comparison with opioid agonist treatment. The results of this study hold the promise to guide planned future studies examining the use of both XR-NTX and other agonist medications in the context of best practice treatment for OUD in pregnancy in order to improve long-term maternal and infant outcomes.