Publication Date

5-2023

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Abstract

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder diagnosed in children with painful or difficult swallowing, vomiting, or poor weight gain.  Current treatment models adopt a trial-and-error approach in regard EoE treatment, including restrictive elimination diets, proton pump inhibitors, and topical budesonide. This approach can delay effective treatment which increases risk of disease progression and increases medical costs to families for frequent clinic visits and endoscopy.   Objectives/Goal: The objective of this study is to determine the CYP3A5 genotype and expression of patients with eosinophilic esophagitis to discover which patients will respond to standard dosing of topical budesonide treatment (1, 2). Budesonide is a known drug substrate of CYP3A5 protein and single polymorphic changes are known to affect drug metabolism.  By determining the CYP3A5 genotype, we aim to correlate treatment response to topical budesonide treatment, leading to more targeted and individualized dosing of budesonide.  Allelic variant *1 (wild-type) has shown high substrate metabolism (1). Allelic variant *3 (most common), *6 , *7 have shown reduced substrate metabolism (1).  The ultimate goal of this study is to aid in the development of a simple serum test to check a patients’ CYP3A5 genotype at the time of EoE diagnosis, prior to initiation of topical budesonide.  Methods/Design: This is a single center retrospective study ongoing at Children’s Mercy Hospital in Kansas City, Missouri using serum and esophageal tissue samples from the already established, ongoing Gastroenterology Repository for Information in Pediatrics biorepository (GRIP) from patients <20 years old, enrolled from 8/1/2017 to 11/1/2022.   For this interim analysis, we had samples from 22 patients for genotyping and mRNA extraction.  Digital droplet PCR (ddPCR) was used for mRNA quantification.   Results: Of the 22 samples, nineteen had *3/*3 CYP3A5 alleles (86.3%), two had *1/*1 alleles (9%), and one had *1/*3 alleles (4.5%).  CYP3A5 ratios were performed, and the initial results of this small sample size so far show that expression does not vary between genotype.  Compared to CYP3A4, there is more CYP3A5 expression in the esophagus than CYP3A4, as noted in prior studies in adults. ddPCR was able to successfully measure CYP3A5 expression in esophageal biopsies confirming this as a valuable tool to quantify mRNA in these small tissue samples.  Conclusions: These initial results are consistent with already published data and will help lay the groundwork for larger, more in-depth studies.  We anticipate more data forthcoming, as the collection of consented patients is ongoing. Future, larger prospective studies are needed to further propagate the development of precision therapeutics of budesonide in EoE patients.

Disciplines

Gastroenterology | Pediatrics

Notes

Presented at Digestive Diseases Week (DDW) 2023; Chicago, IL; May 6-9, 2023.

Drug metabolizing enzymes and transporters may help determine effective budesonide dosing in EoE

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