Exogenous and Endogenous Biomarkers of CYP2D6 Variability in Pediatrics

描述（由申请人提供）：细胞色素P450 2D 6（CYP 2D 6）参与约25%临床使用药物的代谢，其中几种药物常用于不同年龄的儿童。CYP 2D 6基因有几种变体形式，与该基因的“正常”版本相比，这些变体形式与无活性或活性降低相关。虽然CYP 2D 6的基因检测变得越来越容易，但仅用遗传信息指导药物治疗在儿童中可能是不够的，因为基因型-表型关系可能受到出生和青春期之间发生的发育变化的影响。本提案的目的是研究个体发育和遗传变异在学龄儿童和青少年中观察到的CYP 2D 6活性变异性中的相对作用，并评估观察到的变异性的功能后果。为了实现这些目标，共180名6至15岁的儿童和青少年，包括初步诊断为注意缺陷多动障碍（ADHD; n=60）的患者和年龄和性别匹配的对照组（n=120），将每6个月测量一次CYP 2D 6活性，持续3年（目标1）。活性测量将使用非处方止咳剂，美沙芬或“DM”，一种用于确定CYP 2D 6表型的标准探针。该程序包括给予0.5 mg/kg剂量的DM，并在随后的4小时内收集尿液。根据尿样中DM和CYP 2D 6产生的代谢产物右啡烷（DX）的相对量，指定CYP 2D 6活性或“代谢者”状态。目的2将检验以下假设：基于目的1采集的尿液样本中存在的代谢组学生物标志物模式，可以将CYP 2D 6弱代谢者与强代谢者区分开来。在目标3的研究中，将使用的DM将含有稳定的碳同位素（[13 C]），以确定是否可以快速进行基于办公室的CYP 2D 6评估。本试验的原理是通过CYP 2D 6介导的[13 C]-美沙芬O-去甲基化释放的[13 C]-甲基在呼气中以[13 C]O2形式出现，称为“呼吸试验”。最后，将通过比较从呼吸试验数据分布的最高和最低20个样本中抽取的两组ADHD快代谢者对非兴奋剂药物托莫西汀（Strattera（R））的全身暴露量，评估CYP 2D 6活性（目的4）的功能后果。最终，研究的目标是通过为个体患者选择适当剂量的正确药物来个性化儿童药物的使用。 公共卫生相关性：细胞色素P450 2D 6（CYP 2D 6）是体内一种重要的酶，用于分解各种年龄儿童常用的许多药物。本提案的目的是使用非处方咳嗽抑制剂，美沙芬或“DM”（确定CYP 2D 6表型的标准探针），研究学龄儿童和青少年CYP 2D 6活性中发育和遗传变异的相对作用。在研究设计中嵌入了子研究，以研究DM呼吸试验作为CYP 2D 6活性快速测试的潜力，该测试可在医生办公室进行，以及寻找反映酶活性差异的正常身体副产物。最终，研究的目标是通过为个体患者选择适当剂量的正确药物来个性化儿童药物的使用。

DESCRIPTION (provided by applicant): Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of approximately 25% of drugs used clinically several of which are commonly used in children of various ages. The CYP2D6 gene has several variant forms that are associated with no activity or reduced activity compared to the "normal" version of the gene. While genetic testing for CYP2D6 is becoming more accessible, guiding drug therapy with genetic information alone may not be sufficient in children as the genotype-phenotype relationship may be influenced by developmental changes that occur between birth and adolescence. The purpose of this proposal is to investigate the relative roles of ontogeny and genetic variation in the observed variability in CYP2D6 activity in school- aged children and adolescents, and to assess the functional consequences of the observed variability. To achieve these goals, a total of 180 children and adolescents from 6 to 15 years of age, consisting of patients with a primary diagnosis of attention deficit-hyperactivity disorder (ADHD; n=60) and age- and sex-matched controls (n=120), will have their CYP2D6 activity measured every 6 months for 3 years (Aim 1). The activity measurement will utilize the over- the-counter cough suppressant, dextromethorphan or "DM", a standard probe for determining CYP2D6 phenotype. The procedure involves administering a 0.5 mg/kg dose of DM and collecting urine over the following four hours. CYP2D6 activity or "metabolizer" status is assigned based on the relative amounts of DM and the metabolite produced by CYP2D6, dextrorphan (DX), present in the urine sample. Aim 2 will test the hypothesis that CYP2D6 poor metabolizers can be distinguished from extensive metabolizers based on a metabolomic biomarker pattern present in urine samples collected for Aim 1. In the study for Aim 3, the DM to be used will contain a stable isotope of carbon ([13C]) to determine if a rapid, office-based assessment of CYP2D6 is feasible. The principle of this test is that the [13C]-methyl group released by CYP2D6-mediated O-demethylation of [13C]-dextromethorphan appears in expired air as [13C]O2, referred to as a 'breath test'. Finally, the functional consequences of CYP2D6 activity (Aim 4) will be assessed by comparing the systemic exposure to the non-stimulant drug atomoxetine (Strattera(R)) in two groups of ADHD extensive metabolizers drawn from the highest and lowest 20th percentiles of the breath test data distribution. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients. PUBLIC HEALTH RELEVANCE: Cytochrome P450 2D6 (CYP2D6) is an important enzyme in the body for breaking down many medications that are commonly used in children of various ages. The purpose of this proposal is to investigate the relative roles of development and genetic variation in CYP2D6 activity in school-aged children and adolescents using the over-the-counter cough suppressant, dextromethorphan or "DM", a standard probe for determining CYP2D6 phenotype. Embedded in the study design are sub-studies to investigate the potential of a DM breath test to serve as a rapid test of CYP2D6 activity that may be performed in doctors' offices as well as a search for normal body by-products that reflect differences in enzyme activity. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients.