Pharmacometric approaches to precision optimization of ivacaftor response in cystic fibrosis patients

精确优化囊性纤维化患者 ivacaftor 反应的药理学方法

• 批准号: 10349477
• 负责人: Jennifer S Guimbellot
• 金额: $ 17.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349477
• 关键词: Address; Affect; Affinity; Aftercare; Alabama; Asthma; Bicarbonates; Binding; Biological Markers; Body mass index; CYP3A4 gene; Career Mobility; Caring; Cells; Cessation of life; Childhood; Chlorides; Chronic Obstructive Pulmonary Disease; Clinical Data; Clinical Research; Clinical Trials; Clinical effectiveness; Combined Modality Therapy; Complement; Complex; Conduct Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P450; DNA; Data; Defect; Dependence; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Environment; Enzymes; Epithelial; Epithelial Cells; Exposure to; Faculty; Family; Frequencies; Functional disorder; Future; Genetic; Genetic Variation; Genotype; Goals; Hepatic Tissue; Homeostasis; Human; Impairment; In Vitro; Individual; Knowledge; Life; Lung; Lung infections; Measurement; Measures; Medical; Mentors; Metabolism; Methods; Molecular Target; Mucous body substance; Mutation; Nutritional status; Parents; Patient Care; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacologic Substance; Pharmacology; Phenotype; Physicians; Pilot Projects; Plasma; Population; Positioning Attribute; Precision therapeutics; Production; Prospective Studies; Protein Isoforms; Proteins; Pulmonology; Recombinants; Regulator Genes; Research; Scientist; Single Nucleotide Polymorphism; Spirometry; Testing; Therapeutic; Thick; Tissues; Training; Universities; VX-770; Variant; airway epithelium; base; burden of illness; career; career development; clinical efficacy; cystic fibrosis patients; drug efficacy; drug metabolism; enzyme activity; experience; genetic variant; individual patient; medical schools; member; monolayer; novel; novel therapeutics; pediatric department; pharmacometrics; pulmonary function; recruit; response; restoration; skills; statistics; success; treatment optimization; treatment response

Cystic fibrosis (CF) is an autosomal recessive disorder caused by dysfunction of the CF Transmembrane Conductance Regulator (CFTR) channel. The care of patients with CF has rapidly evolved with the development of CFTR modulators, novel pharmaceuticals that address the basic CF defect and restore CFTR function. Despite the success of one of these, the potentiator ivacaftor, there is still pronounced variance in drug efficacy, as measured in individuals’ phenotypic response to therapy and their in vitro cellular response when assessed with cell-based biomarkers. Ivacaftor is metabolized by cytochrome P450 (CYP3A enzymes), which are responsible for both hepatic and tissue-specific metabolism, including in airway epithelia. Genetic variation in these enzymes cause altered activity, resulting in variation in efficacy in many drugs. The preliminary data demonstrate CYP3A variants may be associated with drug efficacy, and the ability to detect ivacaftor metabolism in vitro in individual patients’ epithelia that the applicant personally co-developed. To maximize efficacy of ivacaftor, and thus, any therapy including it, it is essential to understand pharmacogenetics and effect of variability of CYP3A enzyme activity on the metabolism of ivacaftor. The Specific Aims are: 1) conduct a pilot study in people to determine population pharmacokinetics of ivacaftor in plasma and epithelia, and correlate drug exposure with drug response 2) to determine frequencies of genetic variants of these enzymes in the CF population and measure association with clinical efficacy; 3) compare the contribution of CYP3A isoforms to ivacaftor metabolism and understand impact in primary epithelial cells on CFTR activity. Ivacaftor is a significant component of many combination therapies, so understanding its variation in metabolism and impact on efficacy is the first key step to understanding pharmacogenetics in complex combinations, and will set the stage for an independent career focused on precision-directed therapeutics in CF. The applicant has dedicated her professional life to becoming a physician-scientist, studying pediatric pulmonology in general and cystic fibrosis in particular. To achieve this, she accepted a faculty position at the University of Alabama at Birmingham, where a supportive research environment in the Department of Pediatrics and School of Medicine, as well as the Gregory Fleming James Cystic Fibrosis Research Center, has made career advancement and approach to independence possible. To accomplish the goals of this research, the candidate has assembled a mentoring team with decades of experience in clinical trials, pharmacology, genetics, statistics, pharmacogenetics, and drug metabolism to advise and guide her during her career development. She also proposes to undertake formal training in pharmacology, advanced statistics, clinical trial conduct, and genetics to complement her prior medical and graduate studies and acquire the relevant skills to transition to independence.

囊性纤维化是一种常染色体隐性遗传病，由囊性纤维化跨膜功能障碍引起。 电导调节器(CFTR)通道。慢性萎缩性胃炎患者的护理随着 CFTR调节剂的开发--一种解决基本CFT缺陷并恢复CFTR的新型药物 功能。尽管其中一种增效剂IVAKAFTOR取得了成功，但在 药物疗效，通过个体对治疗的表型反应和体外细胞反应来衡量 当用基于细胞的生物标志物进行评估时。异烟肼由细胞色素P450(细胞色素P450 3A酶)代谢， 它们负责肝脏和组织的特异性代谢，包括在呼吸道上皮细胞中。遗传 这些酶的变异会导致活性改变，导致许多药物的疗效不同。这个 初步数据显示，CYP3A变异可能与药物疗效和检测能力有关 异烟肼在个体患者的上皮细胞中的体外代谢，申请者本人共同开发。至 最大限度地提高异烟肼的疗效，因此，包括它在内的任何治疗方法，都必须了解 药物遗传学及细胞色素P3A酶活性变异对维卡他代谢的影响。这个 具体目标是：1)在人体内进行一项初步研究，以确定伊伐他在 血浆和上皮细胞，并将药物暴露与药物反应相关2)以确定遗传基因的频率 这些酶在CF人群中的变异并测量与临床疗效的相关性；3)比较 细胞色素P3A亚型在血管内皮生长因子代谢中的作用及其对血管内皮生长因子的影响 Cftr活动。IVacaftor是许多联合疗法的重要组成部分，因此了解其 代谢的变化和对疗效的影响是理解药物遗传学的第一个关键步骤。 复杂的组合，并将为专注于精确定向的独立职业生涯奠定基础 治疗学在慢性阻塞性肺疾病。 申请者将她的职业生涯献给了成为一名内科科学家，研究儿科 一般是肺病，尤其是囊性纤维化。为了实现这一目标，她接受了在 阿拉巴马大学伯明翰分校，那里的系有支持性的研究环境 儿科和医学院，以及格雷戈里·弗莱明·詹姆斯囊性纤维化研究中心， 使职业发展和走向独立成为可能。为了实现这一目标 研究方面，候选人组建了一支在临床试验方面拥有数十年经验的指导团队， 为她提供药理学、遗传学、统计学、药物遗传学和药物代谢方面的建议和指导 职业发展。她还建议接受药理学、高级统计学、 临床试验指导和遗传学，以补充她以前的医学和研究生学习，并获得 具备向独立过渡的相关技能。