Effect of CYP2C19 *2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects. • It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians. • Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet. WHAT THIS STUDY ADDS • In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated. • This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid‐inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese. AIMS To investigate the impact of CYP2C19 mutations *2‐*6 and *17 on acid‐inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians. METHODS CYP2C19 genotyping for *2–*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6. RESULTS For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid‐inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid‐inhibition after O20 and P40. *1/*2 genotype showed significant acid‐inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid‐inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid‐inhibitory effect after repeated dosing with L15 and O10. CONCLUSIONS Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid‐suppression therapy, especially during the first days of treatment or with on‐demand therapy.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…That the *17 haplotype is associated with enhanced CYP2C19 activity and reduced PPI exposure is supported by several studies. For example, individuals with *17 allele had lower plasma concentrations of pantoprazole compared to NM [7,57,58]. Hunfeld et al investigated the effect of CYP2C19 variants: *2–*6 and *17 on PK parameters of different doses of PPIs (omeprazole 10 mg and 20 mg, lansoprazole 15 mg and pantoprazole 40 mg, Table 3) and percentage of time with intragastric pH > 4 post PPI administration [58].…”

“…For example, individuals with *17 allele had lower plasma concentrations of pantoprazole compared to NM [7,57,58]. Hunfeld et al investigated the effect of CYP2C19 variants: *2–*6 and *17 on PK parameters of different doses of PPIs (omeprazole 10 mg and 20 mg, lansoprazole 15 mg and pantoprazole 40 mg, Table 3) and percentage of time with intragastric pH > 4 post PPI administration [58]. While individuals with IM phenotype demonstrated significant acid suppression after a single-dose treatment with lansoprazole 15 mg or omeprazole 10 mg, those with NM and RM phenotypes showed significant acid reduction (pH>4) only after repeated PPI treatment with omeprazole 20 mg or pantoprazole 40 mg.…”

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

“…17,19,21,22 In contrast to defective CYP2C19*2 and *3 alleles, CYP2C19*17 may thus be associated with ultrarapid metabolism and, therefore, therapeutic failure upon proton pump inhibitor, antifungal or antidepressant treatment. 17,23 The primary aim of this study was to investigate whether the CYP2C19*17 genotype is also correlated with altered imipramine pharmacokinetics. In order to do so, we assessed the novel CYP2C19 polymorphism *17 and measured steady-state imipramine and desipramine plasma concentrations in a large group (n ¼ 178) of depressed patients on imipramine, taking into account CYP2C19*2 and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41, and gene duplication).…”

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

“…As a drug class, the PPIs are well characterized in terms of their pharmacokinetics, absorption, distribution, metabolism, and excretion properties. For example, it is known that PPIs undergo extensive metabolism by cytochromes P450 (P450s), and that CYP2C19 phenotype substantially influences pharmacokinetics, pharmacodynamics, and clinical outcomes (e.g., speed and degree of gastric acid suppression) (Li et al, 2004;Baldwin et al, 2008;Hunfeld et al, 2008;Shi and Klotz, 2008). In a crowded market, therefore, a considerable effort has been made to differentiate the various PPI class members on the basis of their pharmacokinetics, efficacy, and drug-drug interaction profile (Andersson et al, 2001;Blume et al, 2006;Shi and Klotz, 2008;Vakily et al, 2009;Ogawa and Echizen, 2010).…”