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.

PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

“…Thus, CYP2C19 genotyping may be useful in personalizing PPI dosing, though it is not broadly utilized in practice likely due to a lack of knowledge of the association and how to use genotype to guide prescribing. However, evidence review and guidelines for the use of CYP2C19 testing for PPI therapy are forthcoming by CPIC …”

Novel Implementation of Genotype‐Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial

“…29 Across populations, 33% will carry one or more increased function alleles and be at risk for decreased PPI concentrations, whereas 30% will carry one or more decreased function alleles and be at risk for increased PPI concentrations. 30,31 Although PPIs are believed to be highly effective and safe, numerous studies have reported lower blood levels and higher treatment failures in RM and UM phenotypes compared with NM phenotypes. 30,[32][33][34] Additionally, some studies have linked PPI-associated respiratory infections to CYP2C19 PM phenotype.…”

“…Carriage of one or two no function alleles defines intermediate metabolizer (IM) and poor metabolizer (PM) phenotypes, respectively, carriage of one or two increased function alleles defines rapid metabolizer (RM) and ultrarapid metabolizer (UM) phenotypes, respectively, and carriage of no variant alleles defines the normal metabolizer (NM) phenotype . Across populations, 33% will carry one or more increased function alleles and be at risk for decreased PPI concentrations, whereas 30% will carry one or more decreased function alleles and be at risk for increased PPI concentrations …”

Personalized therapy for Helicobacter pylori: CYP2C19 genotype effect on first‐line triple therapy

“…The presence of CYP2C19 *2 and CYP2C19 *3 polymorphisms predicts individual metabolizer phenotype. In 2006, CYP2C19*17 allele was identified, whose function is clinically important because the presence of individuals with two copies of *17 is classified as ultra‐rapid metabolizers (UM), with an ability to metabolize PPIs faster than extensive metabolizers . While heterozygote individuals with one normal activity allele and one variant allele associated with increased activity (*17), CYP2C19 *1/*17 are considered extensive metabolizers (EM) although this continues to be under study .…”

“…In 2006, CYP2C19*17 allele was identified, whose function is clinically important because the presence of individuals with two copies of *17 is classified as ultra‐rapid metabolizers (UM), with an ability to metabolize PPIs faster than extensive metabolizers . While heterozygote individuals with one normal activity allele and one variant allele associated with increased activity (*17), CYP2C19 *1/*17 are considered extensive metabolizers (EM) although this continues to be under study . Clinical implication of CYP2C19 *17/*17 polymorphism relies on the following: If PPIs are quickly metabolized, standard PPIs dose fails to adequately suppress acid secretion, and H pylori eradication therapy will be less effective if the microorganism is sensitive to antibiotics .…”