GOLDILOKs Project 1: Clinical

GOLDILOKs 项目 1：临床

• 批准号: 9976572
• 负责人: Sarah Soden
• 金额: $ 34.94万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976572
• 关键词: Adverse effects; Attention deficit hyperactivity disorder; Biological Markers; CYP2D6 gene; Caliber; Characteristics; Child; Childhood; Clinical; Clinical assessments; Data; Dose; Drug Exposure; Drug Kinetics; Drug Prescriptions; Drug Targeting; Failure; Foundations; Genetic; Genetic Variation; Genome; Genomics; Growth; Guidelines; Human; Individual; Individual Differences; Investigation; Knowledge; Link; Neurotransmitters; Norepinephrine; Outcome Measure; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physicians; Plasma; Publishing; Pupil; Research Design; Strattera; Therapeutic; Translating; Variant; Weight; atomoxetine; base; dose individualization; drug clearance; in vivo; inter-individual variation; metabolomics; neurobehavioral disorder; noradrenaline transporter; pharmacokinetic model; precision drugs; predicting response; presynaptic; response; targeted treatment

Knowledge is limited regarding how ontogeny and genetic variation influence the expression of drug targets and thereby contribute to variability in drug response in children. One challenge in designing studies to acquire this knowledge is the extensive variability in drug exposure that occurs in vivo, especially when drug clearance is dependent on a polymorphically expressed pathway. For example, recently published data by our group demonstrated a 30-fold difference in systemic exposure between CYP2D6 poor and ultrarapid metabolizers administered the same weight-based dose (0.5 mg/kg) of atomoxetine (ATX), a medication used to treat ADHD. Therefore, we propose that by eliminating inter-individual differences in dose-exposure we can identify patient-specific characteristics that are predictive of response thereby creating a foundation for personalized drug dosing guidelines. The aims of this project are to 1) identify the inherent characteristics of children that segregate with ATX clinical response phenotypes, and 2) translate our understanding of the individual characteristics that drive the ATX dose-exposure relationship to target therapeutic exposures prior to a child's first dose. These aims will be accomplished by an investigation that employs an individual genome-ontogeny informed pharmacokinetic (iGO-PK) model to control ATX exposure between patients with state-of-the-art measures of outcome including pharmaco metabolomic signatures, biomarkers of neurotransmitter activity, such as plasma dihydroxyphenylglycol (DHPG) and change in pupil diameter as an indicator of central norepinephrine transport (NET) inhibition by ATX, as well as comprehensive clinical assessment. The proposed study will establish a new investigational paradigm that can be generally applied to medications used for a diverse array of pediatric indications, and that allows physicians to choose the safest and most effective dose of any drug that they prescribe for children.

知识是关于个体发育和遗传变异如何影响药物表达的知识 靶标，从而导致儿童药物反应的变化。一个挑战 设计研究以获取这些知识的是发生药物暴露​​的广泛差异 体内，尤其是当药物清除率取决于多态表达的途径时。为了 示例，我们小组最近发布的数据证明了系统性的30倍差异 CYP2D6较差和超芯片代谢物之间的暴露与基于重量的相同重量 剂量（0.5 mg/kg）的原子苷（ATX），一种用于治疗多动症的药物。因此，我们提出 通过消除剂量暴露的个体间差异，我们可以识别患者特异性 可以预测响应的特征，从而为个性化药物创造基础 给药指南。该项目的目的是1）确定儿童的固有特征 与ATX临床反应表型分离，2）转化了我们对 将ATX剂量暴露与目标治疗的剂量暴露关系的个体特征 在孩子的第一次剂量之前进行暴露。这些目标将通过调查来实现 采用单独的基因组 - 直接知情药代动力学（IGO-PK）模型来控制ATX 具有最先进的预后措施的患者（包括Pharmaco）的暴露 代谢组学特征，神经递质活性的生物标志物，例如等离子体 二羟基苯基甘油（DHPG）和瞳孔直径的变化作为中央的指标 用ATX抑制去甲肾上腺素运输（净），以及全面的临床评估。 拟议的研究将建立一个新的研究范式，通常可以应用于 用于各种儿科适应症的药物，这使医生可以选择 他们为儿童开出的任何药物中最安全，最有效的剂量。