Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

ABSTRACT

Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism.

Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy.

Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

KEYWORDS:

• CYP2C19
• genotype
• proton pump inhibitors
• precision medicine
• pharmacogenetics

Article Highlights

• PPIs are commonly used for acid related disorders, yet variable responses exist

• PPIs are metabolized to a varying degree by CYP2C19

• The difference in response or adverse events is related to the variability in CYP2C19, the gene encoding CYP2C19

• Large body of evidence document the effect of genotype variability on PK/PD and therapeutic outcomes of PPIs

• Large epidemiological studies document a relationship between dose and PPI-related adverse events, which suggest the plausible relation between CYP2C19, PPI drug concentrations and adverse events

• Genotype-guided dosing holds a promise of improving therapeutic outcomes and minimizing adverse events

• Clinical Implementation of CYP2C19 in PPI therapy have started and data documenting its usefulness are likely in the near future

This box summarizes key points contained in the article.

Acknowledgments

N El Rouby would like to thank Donald Max Smith III, Pharm D, from the UF Health Personalized Medicine Program, for his useful discussions.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Grant funding from the National Institutes of Health HG007629 to J A Johnson and J J Lima as part of NHGRI’s IGNITE Network provided partial support for the effort of these authors in preparation of the manuscript.