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

缓释纳曲酮对阿片类药物使用障碍孕妇的安全性、药代动力学和疗效

• 批准号: 10405099
• 负责人: Elisha Wachman
• 金额: $ 61.37万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405099
• 关键词: Adverse effects; Aftercare; Age-Months; Agonist; Alleles; Animals; Biological Assay; Birth; Blood; Boston; Brain; Breast Feeding; Buprenorphine; Caring; Cohort Studies; DNA Methylation; Data; Development; Dose; Drug Kinetics; Effectiveness; Enrollment; Epigenetic Process; Excretory function; Exposure to; Female of child bearing age; Fetal Development; Fetal Distress; Fetus; Future; Genes; Genetic; Genomics; Growth; Hour; Human; Human Milk; Hydrocortisone; Infant; Investigation; Kidney; Knowledge; Lactation; Left; Life; Measures; Medical Societies; Medical center; Metabolism; Methadone; Methylation; Modification; Monitor; Mothers; Naltrexone; Names; Neonatal Abstinence Syndrome; Neurodevelopmental Impairment; North Carolina; Opiate Addiction; Opioid; Opioid Antagonist; Opioid agonist; Outcome; Overdose; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Placenta; Plasma; Policy Maker; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Labor; Prospective cohort study; Provider; Public Health; Receptor Gene; Relapse; Risk; Safety; Saliva; Single Nucleotide Polymorphism; Special Population; Time; Umbilical Cord Blood; Uncertainty; Universities; Urine; Woman; addiction; buprenorphine treatment; common treatment; comparative; effective therapy; fetal; genetic variant; genome wide methylation; genome-wide; human data; improved; individualized medicine; infant outcome; maternal outcome; medication-assisted treatment; mu opioid receptors; neonatal outcome; neurodevelopment; novel; opioid agonist therapy; opioid epidemic; opioid use disorder; optimal treatments; patient population; placental transfer; pre-clinical; pregnant; prenatal exposure; prepregnancy; promoter; prospective; safety study; social; standard of care; success

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.

项目摘要 妊娠期阿片类药物使用障碍（OUD）是美国的一场公共卫生危机；目前的护理标准是治疗 使用丁丙诺啡 (BPH) 等阿片类激动剂，可改善妊娠结局，但 新生儿戒断综合征 (NAS) 的相关风险和可能的长期神经发育障碍 结果。阿片类拮抗剂纳曲酮代表了妊娠期 OUD 的一种新治疗选择 这不会使发育中的胎儿接触阿片类药物，从而大大降低了 NAS 的风险，并可能 改善孕产妇和婴儿的结局。初步的动物和人类研究表明影响极小 纳曲酮暴露对妊娠和胎儿结局的影响，但总体缺乏前瞻性研究 人体数据充分评估了安全性、有效性以及孕产妇和婴儿的全方位结局。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 怀孕期间和产后期间的使用情况尚不清楚。我们建议通过以下方式填补这些知识空白 研究纳曲酮对孕妇的安全性、有效性、药代动力学和药物基因组学 使用 OUD，评估整个怀孕期间和怀孕后第一年的综合母婴结局 诞生。我们将招募 50 名在孕前稳定服用缓释纳曲酮 (XR-NTX) 的孕妇 以及来自波士顿医学中心和北卡罗来纳大学的 50 名 BPH 对照女性 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 功效：比较母体结局（安全性、复发、保留护理）、胎儿结局（生长、胎儿 妊娠期间直至产后 12 个月的婴儿结局（NAS、生长、神经发育） 送货; 2) 药代动力学：测定XR-NTX在妊娠期和产后的药代动力学 女性; 3）基因组学：检查遗传变异与表观遗传修饰之间的关联 mu-阿片受体 (OPRM1) 基因，以及 XR-NTX 治疗后整体 DNA 甲基化的变化 母亲、胎盘和婴儿内的 BPH； 4) 母乳：测量母乳中的浓度 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，使用 OUD 可以改善孕产妇和婴儿的结局。这 这项研究的结果有望指导未来计划的研究，检查 XR-NTX 和 妊娠期 OUD 最佳治疗实践中的其他激动剂药物，以改善 孕产妇和婴儿的长期结局。