Pharmacogenomic and Metabolic Optimization of Glucocorticoid Therapy for Asthma

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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.