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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

基本信息

批准号：
10549860
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
项目类别：
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/10549860
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 Dedications Defect Dependence Development Disease Dose Drug Exposure Drug Kinetics Environment Enzymes Epithelial Cells Epithelium Exposure to Faculty Family Frequencies Functional disorder Future Genetic Genetic Variation Genotype Goals Hepatic 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 System Testing Therapeutic Thick Tissues Training Universities VX-770 Variant Viscosity airway epithelium autosome 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

项目摘要

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.

囊性纤维化是由囊性纤维化跨膜功能障碍引起的常染色体隐性遗传病