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Short Communications: Gastroenterology

New Guidance on Cytochrome P450 2C19 Phenotype-based Use of Proton Pump Inhibitors

Sabet, Samie; McGhee, Jessica E.

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Journal of Pediatric Gastroenterology and Nutrition: May 2021 - Volume 72 - Issue 5 - p 697-699
doi: 10.1097/MPG.0000000000003082
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Abstract

What Is Known/What Is New

What Is Known

  • Being a cytochrome P450 2C19 poor or intermediate metabolizer is associated with increased systemic exposure to the cytochrome P450 2C19-metabolized proton pump inhibitors, which potentially puts these individuals at a higher risk for adverse events.
  • Numerous studies in Asian populations have reported decreased efficacy of proton pump inhibitors among cytochrome P450 2C19 normal metabolizers when a higher level of acid suppression is required.

What Is New

  • The new cytochrome P450 2C19 and proton pump inhibitor-dosing guideline was developed based on 244 pediatric and adult studies that incorporated analyses for the association between cytochrome P450 2C19 genotype and proton pump inhibitor pharmacokinetic parameters or proton pump inhibitor-related clinical outcomes.
  • The guideline provides dosing recommendations based on a patient's cytochrome P450 2C19 phenotype.

PURPOSE AND STRUCTURE OF CLINICAL PHARMACOGENETICS IMPLEMENTATION CONSORTIUM GUIDELINES

The objective of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines is to support clinicians with information on how available genotyping test results should be used to optimize pharmacotherapy (1). CPIC, a National Institutes of Health-funded international consortium, has published and updated 25 peer-reviewed, evidence-based gene-drug/drug class guidelines to date. These include publicly available guideline-specific decision support charts and resources that facilitate the incorporation of pharmacogenomics into electronic health records (1). CPIC guidelines follow a standard format of complementing the evidence and recommendations with 2 tables. The first table provides assignment of predicted phenotype based on genotype, and the second table provides dosing recommendations based on the phenotype. In this communication, Table 1 provides a summary of information discussed in the first table of the guideline for CYP2C19 and PPI dosing.

TABLE 1 - Examples of diplotypes for cytochrome P450 2C19-predicted phenotypes
CYP2C19-predicted phenotypes Examples of CYP2C19 diplotypes
Poor metabolizers 2/ 2, 3/ 3, 2/ 3
Intermediate metabolizers 1/ 2, 1/ 3, 2/ 17, 3/ 17
Normal metabolizers 1/ 1
Rapid metabolizers 1/ 17
Ultrarapid metabolizers 17/ 17
CYP2C19 = cytochrome P450 2C19.
The guideline also lists “Likely intermediate” and “Likely poor-metabolizers” phenotypes, which are associated with having 1 or more decreased function alleles. The “Likely” designation is due to availability of limited data on decreased function alleles, such as CYP2C199 allele (2).
For the complete lists of CYP2C19 diplotype-phenotypes and their frequencies, refer to respective tables available on the guideline's website (3).

The present guideline was developed by a panel of 20 experts (2). A literature review was conducted via PubMed for the period of 1966 to April 2018 using keywords focusing on cytochrome P450 2C19 (CYP2C19) and proton pump inhibitors (PPIs). Limiting the search to human studies with English manuscripts, 831 publications were identified. Studies that did not incorporate analyses for the association between CYP2C19 genotype and PPI pharmacokinetic parameters or PPI-related clinical outcomes were excluded. The remaining 244 studies (in pediatrics and adults) were reviewed and included in the evidence tables available in the supplement document accompanying the guideline (3).

THERAPEUTIC RECOMMENDATIONS

Of the 6 PPIs used in clinical practice, omeprazole, pantoprazole, lansoprazole, and dexlansoprazole are extensively metabolized by CYP2C19. Esomeprazole is less dependent on CYP2C19 for metabolism (4,5). Rabeprazole's clearance specifically is not dependent on cytochrome P450 isoenzymes (4). Therefore, the guideline recommendations only apply to omeprazole, pantoprazole, lansoprazole, and dexlansoprazole (2).

Repeated studies have associated adverse events, such as infections, kidney disease, and bone fractures with long-term use of PPIs (4). CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) may be at a higher risk for these adverse events because of higher PPI systemic exposure (2,6–8). The data on association of these adverse events and CYP2C19 phenotype is still emerging, which makes a strong dosing recommendation difficult (9–10). A 50% dose reduction after achieving initial efficacy can be, however, considered for IMs and PMs who need chronic therapy (>12 weeks) (2). This recommendation is based on moderate-to-strong evidence of decreased PPI metabolism among these phenotypes (2,3). Studies have also shown IMs and PMs are therapeutically advantaged compared with normal metabolizers (NMs) achieving higher and longer gastric acid suppression (11–13). The expectations for the NMs would be to have a normal PPI metabolism but numerous studies in Asian populations (Guideline Supplement Tables 1–4) have reported decreased efficacy of PPIs in CYP2C19 NMs in the settings where a higher level of acid suppression is required (eg, Helicobacter pylori eradication and erosive esophagitis) (2,3). Therefore, the guideline recommends clinicians to consider increasing the recommended dose for these indications by 50% to 100% to enhance treatment efficacy (2). Studies on effects of CYP2C19 rapid and ultrarapid metabolism on PPI systemic exposure and efficacy are limited because of comparatively recent discovery of the CYP2C19∗17 allele (an increased function allele that is responsible for rapid and ultrarapid phenotypes) (14). Low PPI systemic exposure is, however, documented in ultrarapid metabolizers (UMs) compared with NMs, IMs, and PMs (Guideline Supplement Tables 1–3) (2,3). Subsequently, the recommendations are to consider a 50% to 100% dose increase for H pylori or erosive esophagitis treatment for rapid metabolizers (RMs) and a 100% dose increase regardless of the indication for UMs (2). Whenever a 50% to 100% increase in a PPI dose is indicated, the guideline recommends twice daily or more frequent intervals of dosing to enhance PPI efficacy as supported by H pylori treatment studies (2).

PEDIATRIC-SPECIFIC CONSIDERATIONS

Emerging evidence from pediatric studies include decreased PPI efficacy among RMs and UMs and a higher rate of respiratory and gastrointestinal infections among PMs (9–10,15–19). Other studies have associated additional adverse effects with PPI therapy, such as malabsorption, bone fracture, and chronic kidney disease (2). Although CYP2C19 activity is very low before 3 months of age, it reaches a level similar to adults after this age (2). An increasing number of publications have demonstrated the influence of CYP2C19 genetic diversity on PPI metabolism and treatment outcomes in children greater than 1 year of age (2). Consequently, the guideline panel extends its recommendations to pediatric patients as well. The panel, however, states that it is difficult to support these recommendations for preterm infants and infants younger than 3 months of age because of very low clearance of PPIs in neonates (2).

DRUG-DRUG INTERACTIONS AND PHENOCONVERSION

The CPIC guideline for CYP2C19 and PPI dosing includes a discussion of the drug-drug interactions that can particularly become important in the presence of certain phenotypes (2). Cytochrome P450 3A (CYP3A) enzymes play a more significant role as an alternative pathway in metabolism of PPIs for CYP2C19 IMs and PMs. Therefore, CYP3A strong inhibitors (eg, voriconazole, itraconazole, verapamil) can further increase the risk of adverse effects from PPIs in these vulnerable groups. In addition, strong inhibitors of CYP2C19, such as fluconazole or inducers of CYP2C19 and CYP3A, such as rifampin can cause phenoconversion leading to increased systemic exposure of PPIs or reduced efficacy, respectively.

PHENOTYPE FREQUENCY IN DIFFERENT ETHNICITIES

When discussing CYP2C19 and PPI dosing, it may help to quantify CYP2C19 phenotype frequencies across different ethnicities. The incidences of IMs and PMs are estimated to be highest among Oceanians (37% and 57%, respectively) followed by different Asian groups (41%–46% and 8%–13%, respectively) (20). The incidences of RMs and UMs are similarly higher among Near Easterns, Europeans, African-Americans/Afro-Caribbean, and Latinos (23%–27% and 3%–5%) (20).

ACCESS TO PHARMACOGENOMIC TESTING

Ideally, testing before initiation of therapy can improve the likelihood of success and decrease the burden of potential adverse effects. In practice, patients may not already have their pharmacogenomic test results and their clinicians must decide whether or not to pursue testing. Pharmacogenomic testing, including CYP2C19 testing, is available through Clinical Laboratory Improvement Amendments-certified laboratories. Third-party reimbursement remains a challenge, although coverage for pharmacogenomic testing has been increasing in recent years while the cost has been decreasing.

CONCLUSIONS

The new CPIC guideline provides a set of recommendations aiming at increasing the safety and efficacy of PPI therapy based on a patient's CYP2C19 phenotype. When starting CYP2C19-metabolized PPIs, consideration should be given to a 100% increase in starting dose regardless of the indication for UMs and a 50% to 100% increase in starting dose for treatment of H pylori or erosive esophagitis for RMs and NMs. These recommendations are to increase the likelihood of efficacy and success with therapy. When continuing CYP2C19-metabolized PPIs for chronic therapy (>12 weeks), a 50% dose reduction should be considered for IMs and PMs to reduce the likelihood of toxicity. Regardless of the action taken, continuation of monitoring for safety and efficacy is imperative.

REFERENCES

1. Guidelines. Clinical Pharmacogenetics Implementation Consortium. Updated August 11, 2020. https://cpicpgx.org/guidelines/. Accessed August 14, 2020
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15. Knebel W, Tammara B, Udata C, et al. Population pharmacokinetic modeling of pantoprazole in pediatric patients from birth to 16 years. J Clin Pharmacol 2011; 51:333–345.
16. Kearns GL, Blumer J, Schexnayder S, et al. Single-dose pharmacokinetics of oral and intravenous pantoprazole in children and adolescents. J Clin Pharmacol 2008; 48:1356–1365.
17. Franciosi JP, Mougey EB, Williams A, et al. Association between CYP2C19∗17 alleles and pH probe testing outcomes in children with symptomatic gastroesophageal reflux. J Clin Pharmacol 2018; 58:89–96.
18. Franciosi JP, Mougey EB, Williams A, et al. Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment. Eur J Pediatr 2018; 177:69–77.
19. Mougey EB, Williams A, Coyne AJK, et al. CYP2C19 and STAT6 variants influence the outcome of proton pump inhibitor therapy in pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2019; 69:581–587.
20. Gene-specific information tables for CYP2C19: frequency table. PharmGKB. Updated June 29, 2020. https://www.pharmgkb.org/page/cyp2c19RefMaterials. Accessed August 14, 2020.
Keywords:

cytochrome P450 2C19; erosive esophagitis; gastroesophageal reflux disease; Helicobacter pylori; pharmacogenomics

Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition