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.

Public Health Relevance

Little is known about the relative levels of P450 enzyme expression in the lungs of children who do and do not respond to inhaled glucocorticoids (GCs), or the contributions of these enzymes to the metabolic breakdown, pharmacological inactivation, systemic toxicity, and eventual clearance of these important therapeutic agents. GCs provide safe and effective therapy for many people with asthma and other diseases, but as many as 50% of people with asthma are resistant to inhaled GCs and experience limited if any actual benefit. The goal of this research is to understand how CYP-dependent metabolism in the lung and elsewhere in the body influences the effectiveness of GCs, and how other genetic factors interact with these CYPs and GCs, providing new and specific criteria that could be used clinically to tailor GC therapy to a patient's specific genetic and disease profile, thereby improving asthma control and reducing the potential for adverse side-effects that could be encountered with GC dose-escalation and/or the concurrent use of multiple asthma medications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM121648-03
Application #
9599465
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2017-01-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112