Omeprazole Therapy and Genotype

Omeprazole (brand name Prilosec) is a first-generation proton pump inhibitor (PPI) used to treat gastroesophageal reflux disease (GERD), gastric ulcers, duodenal ulcers, upper gastrointestinal (GI) tract inflammatory conditions, eosinophilic esophagitis, and erosive esophagitis. Omeprazole is also used in the treatment of hypersecretory conditions, such as Zollinger-Ellison syndrome, and is used with antibiotics to eradicate . Omeprazole reduces the acidity (raises the pH) in the stomach by inhibiting the secretion of gastric acid. The level of individual omeprazole exposure is influenced by several factors, such as the dose administered, amount of drug absorbed, as well as the kinetics of drug metabolism and drug inactivation. Omeprazole is primarily metabolized by the CYP2C19 enzyme. Individuals with increased CYP2C19 enzyme activity (“CYP2C19 rapid and ultrarapid metabolizers”) may have an insufficient response to standard doses of omeprazole because the drug is inactivated at a faster rate. In contrast, individuals who have reduced or absent CYP2C19 enzyme activity (namely, CYP2C19 intermediate and poor metabolizers) have greater plasma concentrations of omeprazole, which is associated with more potent acid suppression. The frequencies of CYP2C19 metabolizer phenotypes vary among global populations. The FDA-approved drug label does not give dosing guidance for CYP2C19 intermediate or ultrarapid metabolizers (1) (Table 1); however, it does recommend a reduced dosage for individuals of Asian descent without regard for CYP2C19 metabolizer status. It is important to note that early PPI research studies investigating the gene were conducted in Asian populations with ultrarapid and rapid metabolizer phenotypes making up only 1.3–4% of Asian populations compared with approximately 20% of non-Asian populations. In 2018, PPI dosing recommendations for all metabolizer phenotypes were published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) (Table 2) (2, 3). For poor and intermediate metabolizers, DPWG recommends no alteration in dosing based on their consensus that higher plasma concentration of omeprazole results in an increase in the therapeutic effectiveness without an increase in side effects. For CYP2C19 ultrarapid metabolizers with infection, DPWG states that the dose of omeprazole should be increased 3-fold for the eradication of infection. For other indications (for example, GERD), the physician should be aware of possible reduced effectiveness if individuals are rapid or ultrarapid metabolizers and consider increasing the dose 3-fold. The CYP2C19 ultrarapid metabolizers should also be advised to contact their doctor if symptoms of dyspepsia persist. In 2020, the Clinical Pharmacogenetics Implementation Consortium (CPIC) evaluated additional data and now recommends that CYP2C19 ultrarapid and rapid metabolizers may require increased doses of omeprazole to achieve desired therapeutic outcomes, whereas CYP2C19 intermediate and poor metabolizers may require reduced dosage for chronic therapy once efficacy has been established (Table 3) (4).