Background and Importance Proton pump inhibitors (PPIs) are hepatically metabolised primarily by the cytochrome P 450 2C19 enzyme. PPIs are generally considered effective, however CYP2C19 genetic polymorphisms may result in patients not responding appropriately to treatment. CYP2C19 genotyping and interpretation of results may be a contribution by pharmacists towards personalisation of PPI therapy.
Aim and Objectives The aim was to determine the prevalence of CYP2C19 genetic polymorphisms in a cohort of patients showing PPI therapy resistance.
Material and Methods Patients diagnosed with gastro-oesophageal reflux disease or peptic ulcer disease and with documented PPI therapy resistance were identified using ambulatory reflux monitoring and endoscopy databases. An EDTA blood sample was collected from each patient, followed by genomic DNA extraction with the QIAcube (Qiagen). CYP2C19 genotyping was performed with real-time polymerase chain reaction on the GeneAmp PCR System 9700 thermal cycler and reverse hybridisation using the TwinCubator with the PGX-CYP2C19 StripAssay® (ViennaLab). Genotypes (phenotypes) were classified as: *1*1 (normal metabolisers, NMs), *1*17 (rapid metabolisers, RMs), *1*2 or *2*17 (intermediate metabolisers, IMs), or *2*2 (poor metabolisers, PMs). The 2021 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline was used for genotype-based dosing recommendations, which suggests that NMs may be at increased risk of therapeutic failure compared to IMs/PMs, RMs are at increased risk of therapeutic failure, while IMs/PMs have increased chance of efficacy but risk potential toxicity.
Results Thirty-eight patients were recruited; all Caucasian; 20 female, mode 50-59 years (n=11). Most patients (n=17) experienced reflux hypersensitivity, followed by persistent oesophagitis despite PPI treatment (n=10). PPI therapy included esomeprazole (n=20), omeprazole (n=16) or lansoprazole (n=2). The majority of patients (n=20) were genotyped as *1*1 (NM), followed by *1/*17 (n=7, RM), *2*17 (n=6, IM), *1*2 (n=4, IM) and *2/*2 (n=1, PM).
Conclusion and Relevance The majority of patients in this study may be (53% NMs) or are (18% RMs) at risk of therapeutic failure, and the guideline recommends considering a dose increase and monitoring for efficacy in these patients. In patients at risk of side-effects (29% IMs, PMs), the guideline suggests reduction in dose and continued monitoring for efficacy. Pharmacist-led CYP2C19 pharmacogenetic testing can be used a tool to guide dosing and monitoring in patients taking PPIs.
Conflict of Interest No conflict of interest