Absorption and Metabolism of Oral Codeine in Mechanically Ventilated Neonates

描述(申请人提供)：了解新生儿和儿童的止痛反应的决定因素仍然难以理解，部分原因是缺乏一个单一的药理学和分子探针来阐明整个发育过程中阿片类药物反应的个体间差异。因此，安全有效的止痛仍然是儿童尚未得到满足的医疗需求。可待因是世界上最常用的阿片类止痛药，具有代谢激活作用，可作为分子探针和新生儿口服止痛剂。NICHD儿科药理研究单位网络(PPRU)提出了一项大型倡议，以评估观察到的新生儿和儿童阿片类药物反应个体间差异的药理学基础。最初，PPRU的9个地点将在机械通气的足月儿和早产儿中进行单剂量、开放标签的临床试验，这些新生儿出生26周，出生体重700克，已经在不同出生年龄接受阿片类药物止痛。这项建议的具体目的有三个：1)确定可待因与出生后和受孕后年龄(PCA)的吸收和生物利用度；2)确定母药(可待因)、其活性代谢物、它们的形成率及其与PCA和PNA的比率；3)确定该人群阿片代谢的相关遗传多态及其与可待因生物处置和药效作用的潜在关系。单次口服可待因后，将采集血液和尿样用于分析可待因及其代谢物。将获得人口学、药代动力学(PK)、药效学(PD)和药物遗传学数据。主要的PK结果是口服可待因的吸收速度和程度，每种代谢物浓度与母药浓度的比率，以及代谢物的形成和清除，特别是吗啡和吗啡-6-葡萄糖醛酸苷作为新生儿成熟度的函数(PNA，PCA)。基因分析将包括CYP2D6和UGT2B7，这两种主要酶参与可待因和吗啡的生物转化。如果新生儿能够吸收和代谢可待因，就有机会使用单个分子探针来阐明所有年龄段的阿片类药物反应的人口学、PK、PD和PG决定因素，并开发合理的方法来管理新生儿和儿童的疼痛。新生儿和儿童的疼痛管理是医疗保健中的一个主要焦点，因此了解疼痛控制的潜在机制对公共卫生具有重要意义。如果新生儿能够吸收和代谢可待因，就有机会使用单个分子探针来阐明所有年龄段的阿片类药物反应的人口学、PK、PD和PG决定因素，并开发合理的方法来管理新生儿和儿童的疼痛。

DESCRIPTION (provided by applicant): Understanding the determinants of analgesic response in newborns and children remains elusive, in part, due to lack of a single pharmacologic and molecular probe to elucidate the interindivual differences in opiod responsiveness across the entire developmental spectrum. Thus, safe and effective analgesia remains an unmet medical need in children. Codeine, the most commonly used opioid analgesic worldwide, undergoes metabolic activation, and can be potentially developed as a molecular probe and as an oral analgesic in neonates. The NICHD Pediatric Pharmacology Research Unit Network (PPRU) proposes a large initiative to evaluate the pharmacologic basis for the observed interindividual differences in opioid responsiveness in newborns and children. Initially, 9 PPRU sites will conduct a single- dose, open-label clinical trial in 64 mechanically ventilated term and preterm neonates born e 26 weeks gestational age with birth weight > 700 grams and who are already receiving an opioid for pain management at various postnatal ages. The specific aims of this proposal are threefold: 1) To determine the absorption and bioavailability of codeine in relation to postnatal and postconceptional age (PCA) 2) to determine the parent drug (codeine), its active metabolites, their formation rates and their ratios in relation with PCA and PNA and 3) to identify relevant genetic polymorphisms of opioid metabolism in this population and their potential relationship to the biodisposition and pharmacodynamic effects of codeine. Following a single oral dose of codeine, blood and urine samples will be collected for assay of codeine and its metabolites.Demographic, pharmacokinetic(PK), pharmacodynamic (PD)and pharmacogenetic data will be obtained. The primary PK outcomes are the rate and extent of absorption of oral codeine, the ratios of the concentration of each metabolite to the concentration of parent drug and the formation and clearances of the metabolites with particular emphasis on morphine and morphine- 6-glucuronide as functions of neonatal maturity (PNA, PCA) . Genotype analysis will comprise CYP2D6 and UGT2B7, the two major enzymes involved in the biotransformation of codeine and morphine. If the newborn infants can absorb and metabolize codeine, there is an opportunity to use a single molecular probe to elucidate the demographic, PK, PD and PG determinants of opioid responsiveness across all ages and to develop rational approaches to the management of pain in newborns and children. Pain management in newborn and children is a primary focus in healthcare, therefore understanding the mechanisms underlying pain control is of significant relevance to public health. If the newborn infants can absorb and metabolize codeine, there is an opportunity to use a single molecular probe to elucidate the demographic, PK, PD and PG determinants of opioid responsiveness across all ages and to develop rational approaches to the management of pain in newborns and children.