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: 10178062
• 负责人: Elisha Wachman
• 金额: $ 62.44万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178062
• 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 怀孕的阿片类药物使用障碍（OUD）是美国的公共卫生危机；当前的护理标准是治疗 用阿片类药物激动剂（例如丁丙诺啡（BPH）），可改善妊娠结局 新生儿禁欲综合征（NAS）和可能​​的长期神经发育的相关风险 结果。阿片类拮抗剂纳曲酮代表了怀孕的新型治疗选择 这不会使发展中心的胎儿接触阿片类药物，从而大大降低了NAS的风险 改善产妇和婴儿的结果。初步动物和人类研究表明影响很小 关于纳曲酮的怀孕和胎儿结局，但总体上缺乏预期 人类数据充分评估了安全性，疗效以及孕产妇和婴儿结果的全范围。另外， 药代动力学，药物基因组学，胎盘转移，母乳转移和纳曲酮的安全性 怀孕期间和产后期间使用的是未知的。我们建议通过 研究孕妇纳曲酮的安全性，功效，药代动力学和药物基因组学 借助Ouds，在整个怀孕期间和之后的第一年评估全面的母亲结局 出生。我们将招募50名孕妇在延长释放的纳曲酮（XR-NTX）上稳定孕前怀孕 以及来自波士顿医学中心和北卡罗来纳大学BPH的50名比较女性 以多为中心的前瞻性比较队列研究。该项目的具体目的是：1）安全性和 功效：比较母亲的结局（安全，复发，护理中的保留），胎儿结局（生长，胎儿 痛苦）和婴儿结局（NAS，生长，神经发育）在怀孕期间直到12个月后 送货; 2）药代动力学：确定怀孕和产后XR-NTX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）基因以及用XR-NTX处理后的全局DNA甲基化变化 和母亲，胎盘和婴儿的BPH； 4）母乳：测量母乳的浓度 XR-NTX和相应的婴儿相对剂量，以确定哺乳期妇女的安全性。我们假设这一点 XR-NTX将被证明是孕妇和产后妇女的安全有效治疗选择 与阿片类药物治疗相比，随着OUD的改善，孕产妇和婴儿的结局得到了改善。这 这项研究的结果有望指导计划的未来研究研究XR-NTX和 在怀孕中对Oud的最佳实践治疗的背景下，其他激动剂药物为了改善 长期母亲和婴儿的结果。