Pharmacogenomic and Metabolic Optimization of Glucocorticoid Therapy for Asthma

哮喘糖皮质激素治疗的药物基因组学和代谢优化

基本信息

批准号：
9751013
负责人：
Christopher A Reilly
金额：
$ 5.3万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751013
关键词：
Acute Adjuvant Therapy Affect Antiinflammatory Effect Archives Asthma Beclomethasone Biochemical Blood Blood specimen Budesonide CYP3A4 gene CYP3A5 gene Caring Child Clinical Code Corticotropin-Releasing Hormone Receptors Cytochrome P450 Data Disease Dose Drug Kinetics Effectiveness Enrollment Enzymes Exhalation Flunisolide Fluticasone propionate Formularies Frequencies Genes Genetic Genetic Diseases Genetic Markers Genetic Variation Genotype Glucocorticoid Receptor Glucocorticoids Goals Health Care Costs Hydrocortisone In Vitro Individual Inhalation Inhalators Insurance Ion Channel Lung Measures Medicine Metabolic Metabolism Monitor NR3C1 gene Nitric Oxide Oral Other Genetics Oxidoreductase Participant Patient Monitoring System Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacology Pharmacotherapy Phenotype Physiological Population Provider Quality of life Recommendation Research Resistance Risk Safety Sampling Self Management Severities Single Nucleotide Polymorphism Spirometry Steroids Symptoms System Testing Therapeutic Agents Time Transcript Triamcinolone Variant airway inflammation antioxidant enzyme base clinically significant cohort cost cost effective cytochrome P450 3A cytokine effective therapy experience genetic profiling health care service utilization improved individual patient medication compliance novel patient response pulmonary function response side effect symptom management symptomatic improvement systemic toxicity tool uptake

项目摘要

Abstract: Personalized glucocorticoid (GC) therapy for asthma and other diseases could become a reality if specific genetic markers were strongly associated with an individual patient's response to therapy. Our studies have identified 2 inactivating single nucleotide polymorphisms (SNPs) in Cytochrome P450 3A4 and CYP3A5 enzymes that show improved responses to inhaled GCs among children with asthma. We propose these SNPs slow airway and systemic clearance of inhaled GCs, prolonging their anti-inflammatory effects, thereby providing superior asthma control. These clinical observations are further supported by in vitro studies of GC metabolism by the CYP3A enzymes. Building upon these exciting findings, we hypothesize that asthma control with GCs can be improved by using a patient's genetic profile for CYP3A and related genes to guide both the selection of an appropriate GC, its dose, and perhaps other adjuvant therapies. We propose to test this hypothesis through the following tasks: 1) Identify additional genotype:inhaled GC efficacy:asthma control correlations in children with asthma; 2) conduct a pharmacokinetic study with patients to measure systemic clearance of fluticasone propionate (FP) and beclomethasone dipropionate (BDP), relative to CYP3A4 and CYP3A5 genotype - specifically the effects of CYP3A4*22 and CYP3A5*3 versus wild-type genotypes, respectively; and 3) demonstrate longitudinal associations between asthma symptom control for medication:genotype combinations using a novel patient monitoring system, the electronic Asthma Tracker (e-AT), to measure medication compliance, combined with physiologic assessments of pulmonary function, which are essential when monitoring sustained responses to drug therapy. The overall objective of this study is to further understand the biochemical relationship and clinical significance of the CYP3A4*22:FP and CYP3A5*3:BDP genotype:asthma control associations and expand these observations to account for other associated genetic variations that impact GC metabolism, efficacy, and asthma care. Inhaled glucocorticoids (GCs) are the primary medications prescribed to control asthma. However, GCs fail to control asthma symptoms in up to 50% of people. Thus, it is critical to understand factors that limit efficacy in order to guide the selection of the best treatment to maximize benefit and reduce healthcare costs. We expect these studies to explain our findings on CYP3A4 and 3A5 and to reveal new relationships between asthma control, GCs and SNPs in various components of the “CYP3A enzyme system” which can be used as a framework to improve asthma care using GCs.

抽象的：个性化糖皮质激素（GC）治疗哮喘和其他疾病的疗法，如果具体的话，可能是现实遗传标记与我们的研究疗法密切相关鉴定出2个灭活单核苷酸多态性（SNP）在细胞色素P450 3A4和CYP3A5中在患有哮喘儿童中吸入的GC的反应改善的酶我们提出了这些SNP。慢速气道和吸入GC的全身清除，延长其抗炎作用，从而提供超元哮喘控制。由CYP3A酶建立了令人兴奋的发现，我们假设使用GCS 可以通过使用遗传概况forp3a和相关基因来改进适当的GC，其剂量，也许是其他辅助疗法。以下任务：1）确定其他基因型：吸入GC功效：儿童哮喘控制性哮喘； 2）与患者进行药代动力学研究相对于CYP3A4和CYP3A5基因型 - 具体来说，CYP3A4*22和CYP3A5*3与野生型基因型的影响；证明药物哮喘症状控制之间的纵向关联：基因型组合使用新型的患者监测系统，电子哮喘跟踪器（E-AT），测量药物合规性，结合对肺功能的生理评估，在监测时至关重要对药物治疗的持续反应。 CYP3A4*22：FP和CYP3A5*3：BDP基因型：哮喘控制的关系和临床意义关联并扩大这些观察结果，以说明影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响的影响影响的影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响帝国影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响影响影响影响影响的影响影响影响影响影响影响影响影响影响影响影响影响影响影响影响的影响影响影响的影响影响影响影响影响影响影响影响帝国的影响影响影响影响影响影响影响影响影响帝国的影响影响的影响影响影响影响帝国代谢，疗效和哮喘护理。但是，哮喘。了解限制功效的因素，以指导选择最佳治疗方法以最大程度地提高利益和降低医疗费用。 “ CYP3A酶系统”的各个组成部分中的哮喘控制，GC和SNP之间的关系可以用作使用GCS改善哮喘护理的框架。