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（OUD）是美国的公共卫生危机;目前的护理标准是治疗 使用阿片类激动剂，如丁丙诺啡（BPH），显示可改善妊娠结局， 新生儿戒断综合征（NAS）和可能的长期神经发育相关风险 后果阿片类拮抗剂纳洛酮是妊娠期OUD的一种新的治疗选择 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， 改善产妇和婴儿的结果。初步的动物和人类研究表明， 纳洛酮暴露对妊娠和胎儿结局的影响，然而，总体上缺乏前瞻性研究。 人类数据充分评估安全性、有效性和母婴结局的全方位。此外该 纳洛酮的药代动力学、药物基因组学、胎盘转移、母乳转移和安全性， 怀孕期间和产后期间使用的药物不详。我们建议填补这些知识空白， 研究纳洛酮对孕妇的安全性、有效性、药代动力学和药物基因组学 使用OUD，评估整个妊娠期和妊娠后第一年的综合母婴结局 出生我们将招募50名在妊娠前接受缓释纳洛酮（XR-NTX）稳定的孕妇 和来自波士顿医学中心和北卡罗来纳州大学的50名BPH对照妇女， 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：比较母体结局（安全性、复发、保留护理）、胎儿结局（生长、胎儿 窘迫）和婴儿结局（NAS，生长，神经发育）在怀孕期间，直到12个月后， 2）药代动力学：测定XR-NTX在妊娠期和产后的药代动力学 3）基因组学：研究遗传变异和表观遗传修饰之间的关联， XR-NTX治疗后μ阿片受体（OPRM 1）基因以及整体DNA甲基化变化 和BPH在母亲，胎盘和婴儿;和4）母乳：为了测量母乳中的 XR-NTX和相应的婴儿相对剂量，以确定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安全有效的治疗选择 与阿片类激动剂治疗相比，OUD的母婴结局得到改善。的 这项研究的结果有望指导计划中的未来研究， 在妊娠期OUD最佳实践治疗的背景下使用其他激动剂药物，以改善 长期母婴结局。

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.