CYP2C19 Genotype Status Research Articles

Impact of CYP2C19 genotype status on clinical outcomes in patients with symptomatic coronary artery disease, stroke, and peripheral arterial disease

Abstract Background Coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD) are clinical manifestations of atherosclerosis. Clopidogrel is widely used for the secondary prevention of atherothrombotic events in these patients. CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. Purpose To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). Methods A comprehensive search in Pubmed, EMBASE and MEDLINE from their inception to April 8th 2022 was performed. For CAD, randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment were included. For stroke and PAD, cohort studies and post-hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. Results Forty-two studies were identified: 11 studies on CAD, 27 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE (RR 0.60, 95% CI 0.43 – 0.83), myocardial infarction (RR 0.53, 95% CI 0.42 – 0.68), and stent thrombosis (RR 0.64, 95% CI 0.43 – 0.94) compared to standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70 – 1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.62, 95% CI 1.24 – 2.11) and recurrent ischemic stroke (RR 2.00, 95% CI 1.49 – 2.67) compared to non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43 – 1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. Conclusion The available evidence in PAD is too limited to draw meaningful conclusions. In stroke patients, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI.

CYP2C19 expression modulates affective functioning and hippocampal subiculum volume—a large single-center community-dwelling cohort study

Given controversial findings of reduced depressive symptom severity and increased hippocampus volume in CYP2C19 poor metabolizers, we sought to provide empirical evidence from a large-scale single-center longitudinal cohort in the community-dwelling adult population—Colaus|PsyCoLaus in Lausanne, Switzerland (n = 4152). We looked for CYP2C19 genotype-related behavioral and brain anatomy patterns using a comprehensive set of psychometry, water diffusion- and relaxometry-based magnetic resonance imaging (MRI) data (BrainLaus, n = 1187). Our statistical models tested for differential associations between poor metabolizer and other metabolizer status with imaging-derived indices of brain volume and tissue properties that explain individuals’ current and lifetime mood characteristics. The observed association between CYP2C19 genotype and lifetime affective status showing higher functioning scores in poor metabolizers, was mainly driven by female participants (ß = 3.9, p = 0.010). There was no difference in total hippocampus volume between poor metabolizer and other metabolizer, though there was higher subiculum volume in the right hippocampus of poor metabolizers (ß = 0.03, pFDRcorrected = 0.036). Our study supports the notion of association between mood phenotype and CYP2C19 genotype, however, finds no evidence for concomitant hippocampus volume differences, with the exception of the right subiculum.

The CYP2C19 polymorphisms effects on H. pylori cure rate in proton pump inhibitor-based therapeutic regimens: An updated meta-analysis

IntroductionCYP2C19 genotypes induce H. pylori eradication rate in the patients receiving PPI-based treatment regimens. The present study aimed to evaluate the effect of CYP2C19 variants on the H. pylori eradication rate in naive patients treated with PPI-based anti-H. pylori therapies. MethodsA computer-assisted comprehensive literature search was done in the Scopus, Pubmed, Embase, and the Cochran Register of Controlled Trials (CENTRAL) databases, for the relevant studies to be collected with no limitation in the language and publication date. All statistic analyses were performed using Comprehensive meta-analysis software. Eradication rate of H. pylori in different CYP2C19 genotypes was measured via event rate; In addition, we pooled the data by the odds ratio with 95% CI to evaluate the effect of CYP2C19 polymorphisms on the changes in the rates of H. pylori eradication as well as sup-grouping analysis for individual PPIs. Publication bias also was assessed via Begg's p-value, Egger's p-value, and funnel the plot. ResultsThe number of studies included in the present one was 38 studies with 7079 data from the patients. H. pylori eradication rates in HomEMs, HetEMs and PMs were 77%, 82.7% and 85.4%, respectively. We observed a significant difference in H. pylori eradication rates between the HomEMs vs. HetEMs (OR: 0.69; 95% CI: 0.57–0.85), HomEMs vs. PMs (OR: 0.57; 95% CI: 0.46–0.72), as well as HetEMs vs. PMs (OR: 0.70; 95% CI: 0.56–0.87). However, the subgroup analysis was performed due to significant heterogeneity. A significantly lower eradication rate in HomEMs vs. HetEMs (OR: 0.34; 95% CI: 0.22–0.52) and HomEMs vs. PMs (OR: 0.22; 95% CI: 0.10–0.47) for Omeprazole as well as HomEMs vs. HetEMs (OR: 0.56; 95% CI: 0.39–0.82) for Lansoprazole or HomEMs vs. PMs (0.57; 95% CI: 0.33–1.00) were observed for Esomeprazole. ConclusionThe H. pylori eradication rate in HomEM, HetEM, and PM was 77%, 82.7%, and 85.4% respectively. Moreover, the clinical efficacy of Omeprazole, Lansoprazole, and Esomeprazole-based first-line therapies is significantly dependent on the CYP2C19 genotype status, while polymorphisms of this gene have no significant effect on the efficacy of Pantoprazole and Rabeprazole-based diets.

Effect of CYP2C19 Genotype on IschemicOutcomes During OralP2Y12Inhibitor Therapy: A Meta-Analysis.

The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel. The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear. Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype. Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p=0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction<0.001). The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

Efficacy and Safety Profile of Z-215 (Azeloprazole Sodium), a Proton Pump Inhibitor, Compared with Rabeprazole Sodium in Patients with Reflux Esophagitis: A Phase II, Multicenter, Randomized, Double-Blind, Comparative Study

BackgroundThe metabolism of many proton pump inhibitors is influenced by CYP2C19 genotype, which is a limitation of their use. ObjectivesTo determine the efficacy and safety profile of Z-215 (azeloprazole sodium) as initial treatment for reflux esophagitis (RE), dose response, and optimal dose compared with rabeprazole sodium (RPZ). MethodsWe conducted an exploratory, multicenter, randomized, double-blind, parallel-group study in Japan. Patients with RE aged ≥20 years were enrolled and randomly assigned to receive 10, 20, or 40 mg Z-215 or 10 mg RPZ (1:1:1:1), and orally administered the respective drug for 8 weeks. The primary efficacy end point was the endoscopic healing rate after 8 weeks of treatment (at Week 8). We also assessed the effects of CYP2C19 genotype. Safety end points were the incidence of adverse events and adverse drug reactions. ResultsFive hundred three patients received the study drugs (10 mg Z-215: 125 patients, 20 mg Z-215: 126 patients, 40 mg Z-215: 126 patients, and 10 mg RPZ: 126 patients). The endoscopic healing rate at Week 8 was above 95% in all groups (10 mg Z-215: 95.2%, 20 mg Z-215: 96.8%, 40 mg Z-215: 95.2%, and 10 mg RPZ: 96.8%). The endoscopic healing rate and serum gastrin levels of the Z-215 groups were not influenced by CYP2C19 genotype. In patients with Grade C/D, the endoscopic healing rate at Week 4 was slightly higher in the 40-mg Z-215 group compared with the other groups. Incidences of adverse events/adverse drug reactions did not markedly differ between the Z-215 and 10-mg RPZ groups. ConclusionsZ-215 was as effective and well tolerated as 10 mg RPZ in the treatment of RE in this selected population. CYP2C19 genotype status may not influence the efficacy and safety of Z-215. There were no clear dose–response effects between Z-215 doses in the endoscopic healing of RE. These findings suggest that Z-215 may be 1 option for the initial treatment of RE. ClinicalTrials.gov identifier: NCT 02463643.

CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence: Analysis of the International Tamoxifen Pharmacogenomics Consortium dataset

The role of cytochrome P450 drug metabolizing enzymes in the efficacy of tamoxifen treatment of breast cancer is subject to substantial interest and controversy. CYP2D6 have been intensively studied, but the role of CYP2C19 is less elucidated, and we studied the association of CYPC19 genotype and recurrence of breast cancer. We used outcome and genotyping data from the large publicly available International Tamoxifen Pharmacogenomics Consortium (ITPC) dataset. Cox regression was used to compute the hazard ratios (HRs) for recurrence. CYP2C19 genotype data was available for 2 423 patients and the final sample cohort comprised 2 102 patients. CYP2C19*2 or *19 alleles did not influence DFS. For the CYP2C19*2 allele, the HR was 1.05 (CI 0.78–1.42) and 0.79 (CI 0.32–1.94) for hetero- and homozygote carriers, respectively. The corresponding HR for hetero- and homozygote carriers of the CYP2C19*17 allele were 1.02 (CI 0.71–1.46) and 0.57 (CI 0.26–1.24), respectively. Accounting for CYP2D6 genotype status did not change these estimates. We found no evidence to support a clinically meaningful role of CYP2C19 polymorphisms and response to tamoxifen in breast cancer patients and, consequently, CYP2C19 genotype status should not be included in clinical decisions on tamoxifen treatment.

Esomeprazole- or Rabeprazole-Based Triple Therapy Eradicated Helicobacter pylori Comparably, Regardless of Clarithromycin Susceptibility and CYP2C19 Genotypes

Introduction: The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori in Japan. Methods: For this multicenter, prospective, randomized, controlled study, we enrolled 219 H. pyloriinfected patients from 6 participating hospitals in Japan. We randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily). Successful eradication was evaluated using the urea breath test at 4 to 8 weeks after completing the eradication therapy. Results: The H. pylori eradication rate according to the PP analyses was 75.0% (95% CI: 65.2%-82.8%) in the EAC group and 71.4% (95% CI: 61.4%- 79.1%) in the RAC group. There were no statistically significant differences between the two groups. The eradication rates did not vary with the CYP2C19 genotype. The eradication rates of the clarithromycin-resistant/ -sensitive strains were, respectively, 45.0% (95% CI: 30.7%-60.2%)/98.0% (95% CI: 88.7%-100%) in the EAC group and 39.5% (95% CI: 25.6%-55.3%)/93.5% (95% CI: 81.9%-98.4%) in the RAC group. The eradication rate of the clarithromycin-sensitive strains was significantly higher than that of the clarithromycin resistant strains in both EAC (P P < 0.001) groups. Conclusion: In conclusion, EAC and RAC therapies for H. pylori show a comparable efficacy regardless of the CYP2C19 genotype and clarithromycin susceptibility status in Japan.Figure 1

In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker

1. TAK-438, vonoprazan fumarate, is a novel orally active potassium-competitive acid blocker, developed as an antisecretory drug. In this study, we investigated the in vitro metabolism of 14C-labeled TAK-438. In human hepatocytes, M-I, M-II, M-III and M-IV-Sul were mainly formed, and these were also detected in clinical studies. N-demethylated TAK-438 was also formed as an in vitro specific metabolite. Furthermore, CYP3A4 mainly contributed to the metabolism of TAK-438 to M-I, M-III, and N-demethylated TAK-438, and CYP2B6, CYP2C19 and CYP2D6 partly catalyzed the metabolism of TAK-438. The sulfate conjugation by SULT2A1 also contributed to the metabolism of TAK-438 to form TAK-438 N-sulfate, and CYP2C9 mediated the formation of M-IV-Sul from TAK-438 N-sulfate. The metabolite M-IV, which could be another possible intermediate in the formation of M-IV-Sul, was not observed as a primary metabolite of TAK-438 in any of the in vitro studies.2. In conclusion, TAK-438 was primarily metabolized by multiple metabolizing enzymes including CYP3A4, CYP2B6, CYP2C19, CYP2D6, and a non-CYP enzyme SULT2A1, and the influence of the CYP2C19 genotype status on gastric acid suppression post TAK-438 dosing could be small. The multiple metabolic pathways could also minimize the effects of co-administrated CYP inhibitors or inducers on the pharmacokinetics of TAK-438.

Esomeprazole- or rabeprazole-based triple therapy eradicated Helicobacter pylori comparably regardless of clarithromycin susceptibility and CYP2C19 genotypes.

The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori (H. pylori) in Japan. We enrolled 219 H. pylori-infected patients, and randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily). The H. pylori eradication rate according to the PP analyses was 75.0% (95% CI: 65.2–82.8%) in the EAC group and 71.4% (95% CI: 61.4–79.1%) in the RAC group. There were no statistically significant differences. The eradication rates of the clarithromycin-resistant/-sensitive strains were, respectively, 45.0% (95% CI: 30.7–60.2%)/98.0% (95% CI: 88.7–100%) in the EAC group and 39.5% (95% CI: 25.6–55.3%)/93.5% (95% CI: 81.9–98.4%) in the RAC group. The eradication rate of the clarithromycin-sensitive strains was significantly higher than that of the resistant strains in both groups. In conclusion, EAC and RAC therapies show a comparable efficacy regardless of the CYP2C19 genotype and clarithromycin susceptibility status in Japan.

High Helicobacter pylori cure rate with sitafloxacin-based triple therapy.

Bacterial resistance of Helicobacter pylori to antibiotics is increasing and it often leads to failure of antibiotic treatment. A new sitafloxacin-based triple therapy was developed to counter this situation; the fluoroquinolone sitafloxacin has a low minimum inhibitory concentration for H. pylori. To investigate the efficacy in Japanese patients of sitafloxacin-based triple therapy and document its efficacy in relation to anti-microbial susceptibility. We investigated the efficacy of a 1-week sitafloxicin-based regimen of rabeprazole 10 mg four times daily (q.d.s.), metronidazole 250 mg twice daily (b.d.) and sitafloxacin 100 mg b.d. in 180 H. pylori-positive Japanese patients (first-line treatment: n = 45, second-line; n = 41, third-line: n = 94). At 8 weeks, patients were given the (13) C-urea breath test to assess eradication status. Eradication rate was 92.2% [95% confidence interval (CI): 87.3-95.7%, 166/180] in intention-to-treat analysis. Although the eradication rate was higher in patients treated with first-line therapy [45/45 (100%, 95% CI: 83.4-100%)] than in those with second- [38/41 (92.7%, 80.1-98.5%)] or third-line therapy [83/94 (88.3%, 80.0-94.0%)], no significant differences were noted with respect to the number of previous therapy attempts (P = 0.054). Eradication rates in patients infected with sensitive- and resistant strains to metronidazole were 96.6% (28/29) and 96.3% (77/80) (P = 0.941), respectively, while rates were 98.4% (60/61) in sitafloxacin-sensitive and 50.0% (1/2) in sitafloxacin resistant strains (P < 0.001). Sitofloxacin-based triple therapy with metronidazole b.d. and rabeprazole q.d.s. achieved an eradication rate exceeding 88%, irrespective of eradication history, CYP2C19 genotype, or metronidazole resistance status.

774 Perceptions of Training Among Program Directors and Trainees in Complex Endosopic Procedures (CEPs): A Nationwide Survey of US ACGME Accredited Gastroenterology Training Programs

Background: Insufficient inhibition of gastric acid during Helicobacter pylori treatment and bacterial resistance to antibiotics frequently results in failure to eradicate infection. Twicedaily dosing (b.i.d.) of a proton pump inhibitor (PPI) using standard eradication therapy has shown difficulty in maintaining high gastric pH values for 24 h in patients. However, four-times-daily dosing (q.i.d.) achieves these goals, irrespective of CYP2C19 genotype status, and might therefore be an optimal regimen for use in eradicating H. pylori infection. The fluoroquinolone sitafloxacin (STFX) was recently reported to have a lower minimum inhibitory concentration for H. pylori compared with levofloxacin and has become clinically available as a third-line treatment and for patients with penicillin allergy. An STFX-based eradication regimen with maintenance of acid inhibition might therefore have a high success rate. We investigated the efficacy of this treatment and maintenance of acid inhibition by PPI q.i.d. treatment. Methods: In 136 H. pylori-positive Japanese patients (for first-line treatment: n=40, second-line: n=30, third-line: n=66), the efficacy of the following treatment regimen was investigated: a PPI (rabeprazole 10 mg, q.i.d.), metronidazole (250 mg, b.i.d.), and STFX (100 mg, b.i.d.) for 1 week, irrespective of CYP2C19 genotype status and numbers of previous eradication therapy. At four to eight weeks after treatment, patients underwent the [13C]-urea breath test to assess successful eradication. Results: First-resistance to antimicrobial agents was 51.4% for clarithromycin, 56.7% for metronidazole and 30.0% for levofloxacin. The intention-to-treat eradication rate in the tailored group was 93.4% (95%CI: 87.8%-96.9%, 127/136). Although the eradication rate in patients treated as first-line therapy (100%, 95%CI: 92.8%-100%, 40/40) was higher than that in those treated as second-line (93.3%, 95%CI: 77.9%-99.2%, 28/30) and third-line therapy (89.4%, 95%CI: 87.8%-96.9%, 59/66), no significant differences were shown among numbers of previous eradication therapy (p = 0.08). The eradication rates were similar among all three CYP2C19 genotype groups (extensive metabolizer, 91.7% [66/73]; intermediate metabolizer, 96.1% [49/51]; poor metabolizer, 91.7% [11/12]), exceeding 90% for all genotypes. Conclusions: A sitafloxacinbased H. pylori eradication regimen based on maintaining acid secretion (rabeprazole 10 mg, q.i.d.) achieved an eradication rate of more than 90%, irrespective of eradication history and CYP2C19 genotype. In addition, as this regimen reduces the cost of CYP2C19 genotyping and culture tests, it might be more cost-effective than CYP2C19 genotype-based treatments.

Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.

To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [C(min)]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and C(min)) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479).

Sa1903 Efficacy of Clarithromycin-Susceptibility Based Tailored Helicobacter pylori Eradication Treatment Maintaining Acid Secretion for a Full 24 Hours

Background: Over the years, the eradication rate of Helicobacter pylori during treatment has gradually decreased for two reasons: increased prevalence of clarithromycin (CAM)-resistant strains and acid inhibition during treatment, as insufficient acid inhibition during treatment makes antimicrobial agents unstable and leads to their degradation in stomach. During treatment, when respective percent time of pH , 4.0 and 24-h pH values of , 10% and . 6.0 were attained, most cases of infection were able to be resolved, irrespective of bacterial susceptibility. However, the optimum regimen of proton pump inhibitors (PPIs) is unknown at present. We therefore assessed acid inhibitory effects of multiple PPI dosing methods with respect to CYP2C19 genotype status and efficacy of CAM-susceptibility-based H. pylori eradication efforts by maintaining acid secretion for a full 24 h. Methods: [Study 1] Using pHmonitoring, we evaluated the efficacy of multiple dosing regimenswith the PPI rabeprazole (40 mg sid, 20 mg bid, and 10 mg qid). [Study 2] A total of 200 H. pylori-positive patients were randomly assigned to the standard regimen group (rabeprazole 10 mg bid, amoxicillin (AMPC) 750 mg bid and CAM 400 mg bid for 1 week) or the tailored regimen group based on bacterial susceptibility to CAM. Patients infected with CAM-sensitive H. pylori were treated with rabeprazole 10 mg qid, AMPC 500 mg qid and CAM 400 mg bid for 1 week, and patients infected with CAM-resistant H. pylori were treated with rabeprazole 10 mg qid, AMPC 500 mg qid, and metronidazole (MNZ) 250 mg bid for 1 week. Results: [Study 1] Respective median 24-h pH values for rabeprazole 40 mg sid, 20 mg bid, and 10 mg qid were 4.8 (3.6-6.4), 5.7 (4.1-7.4), and 6.6 (4.9-8.4). Increasing the dosing times effectively increased pH throughout a 24-h period. In CYP2C19 poor metabolizers, acid inhibition by a PPI was enhanced in comparison with that in CYP2C19 intermediate or rapid metabolizers. Further, rabeprazole 10 mg qid maintained pH . 4 for 24 h in rapid metabolizers. [Study 2] The intention-to-treat eradication rate in tailored regimen group was 96.0% (95% confidence interval [CI]: 90.1%-98.9%, 96/100), which was significantly higher than that in the standard regimen group (70.0%, 95% CI: 60.0%-78.8%, 70/100) (P , 0.001). In the tailored regimen group, the eradication rate in the PPI/AMPC/CAM regimen was 93.2% (95% CI: 83.5%98.1%, 55/59), and that in the PPI/AMPC/MNZ regimen was 100% (95% CI: 93.0%-100%, 41/41). Discussion: Four-times daily dosing of rabeprazole 10 mg achieved potent acid inhibition, including at night, in CYP2C19 rapid metabolizers, suggesting its potential usefulness in patients refractory to PPI therapeutic regimens. Using this PPI qid treatment for all patients made CAM-susceptibility-based H. pylori eradication treatment effective, with an eradication rate exceeding 95%.

Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H+, K+-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

Association of CYP2C19 Genotype With Periprocedural Myocardial Infarction After Uneventful Stent Implantation in Chinese Patients Receiving Clopidogrel Pretreatment

High platelet reactivity (HPR) after clopidogrel treatment is linked to an increased risk of periprocedural myocardial infarction (PMI). The occurrence of PMI that could be associated with CYP2C19 genotype status was our hypothesis. A total of 233 patients with non-ST elevation acute coronary syndromes (NSTACS) undergoing uneventful elective percutaneous coronary intervention were included. Platelet reactivity was assessed by thrombelastograph at 24 h after 300 mg clopidogrel loading. HPR was defined as ≥70% adenosine diphosphate-induced platelet aggregation. The CYP2C19*2 and *3 loss-of-function (LOF) alleles were determined using DNA microarray method. Patients with PMI had significantly higher on-clopidogrel platelet reactivity compared to those without PMI (60.0±24.4% vs. 43.0±24.0%, P<0.001). HPR was more frequently observed in patients with PMI and was the strongest risk factor of PMI in multivariate analysis (OR(adj)=4.348, 95% CI: 1.846-10.241, P=0.001). Furthermore, the incidence of HPR was significantly associated with the carriage of 2 CYP2C19 LOF alleles. Compared with non-carriers, patients carrying 2 CYP2C19 LOF alleles had a 3.000-fold increased risk (95% CI: 1.071-8.400, P=0.037) for PMI in multivariate analysis. However, inclusion of HPR as a covariate in the regression model changed the significant relationship between the carriage of 2 CYP2C19 LOF alleles and PMI. Among Chinese patients with NSTACS, carriers with 2 CYP2C19 LOF alleles are more prone to HPR, which is associated with an increased risk for PMI.

Pharmacokinetics of Tenatoprazole, a Newly Synthesized Proton Pump Inhibitor, in Healthy Male Caucasian Volunteers

The pharmacokinetics of tenatoprazole (CAS 113712-98-4), a newly synthesized proton pump inhibitor, and its metabolites TU-501 (sulfide form) and TU-502 (sulfone form) were investigated in an ascending-dose parallel-group study at the dose levels of 10, 20, 40, 80 and 120 mg. A total of 30 healthy Caucasian male volunteers (6 in each dose group) received a single dose at Day 1 (fasted state) and repeated doses from Day 14 to Day 20. CYP2C19 genotype status was determined in all subjects. Concentrations of tenatoprazole, TU-501 and TU-502 in plasma and urine were measured by a validated HPLC/MS/MS method. The single and multiple-dose study provided reliable tolerance. After the single administrations, plasma concentrations reached a maximum between 2.5 and 4.3 h post dose, and thereafter decreased according to a terminal half live (T1/2) ranging from 4.8 to 7.7 h. Similar T1/2 were obtained on first and the last administration, and the steady state was reached after 5 days. Cmax and AUC increased linearly between 10 to 80 mg. However, with the 120 mg dose, the observed Cmax was higher than expected, especially at steady state. For TU-501 and TU-502 metabolites, Cmax and AUC increased linearly after repeated administration between 40 and 120 mg.

CYP2C19 Genetic Polymorphisms in Patients with Peptic Ulcer Disease and Nonulcer Dyspepsia in Thailand

Purpose: Recently, the CYP2C19 genotype has been found to be an important factor in peptic ulcer healing rate, H. pylori. eradication and has influences on the therapeutic efficacy of proton pump inhibitor. The aim of this study was to investigate CYP2C19 genotype status in patients with peptic ulcer disease and non-ulcer dyspepsia in Thailand. Methods: Clinical information, endoscopic findings and H. pylori infection of all patients were collected between January 2009 and April 2010 in Thammasat University Hospital, Thailand. The upper GI endoscopy was performed in all patients. Three antral biopsies were obtained, one for rapid urease test and culture, one for histopathology and another one for CYP2C19 study. Patients were regarded as H. pylori-positive if at least one of the examinations gave a positive result. The CYP2C19 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism analysis and was classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results: Total 121 patients were enrolled in this study including 61 males and 60 females with mean age of 51.3 years. There were 86 patients with non-ulcer dyspepsia and 36 patients with peptic ulcer disease. The prevalence of CYP2C19 genotype was 45/121 (37.2%) in RM, 65/121 (53.7%) in IM and 11/121 (9.1%) in PM. The prevalence of H. pylori infection was demonstrated in 77.8% in RM, 76.9% in IM and 63.7% in PM without statistical different between each group. However, the prevalence of peptic ulcer disease in CYP2C19 genotype RM and IM was significantly greater than those of genotype PM (29.5% vs 16.7%: P<0.05 and 29.2% vs 16.7%: P<0.05 respectively). Conclusion: CYP2C19 genotype IM was the most common genotype in Thailand followed by genotype RM and PM. Peptic ulcer disease has significant greater prevalence in CYP2C19 genotype RM and IM than those of genotype PM. CYP2C19 genotypes might play a role in the development of peptic ulcer disease and need further studies to clarify this relationship.

Proton Pumps Inhibitors and Clopidogrel Interaction: Effect of Rabeprazole on the Anti-Platelet Function of Clopidogrel in Relation to CYP2C19 Genotype Status. A Prospective, Randomized, 3-way Crossover PK/PD Study in Healthy Subjects

Proton Pumps Inhibitors and Clopidogrel Interaction: Effect of Rabeprazole on the Anti-Platelet Function of Clopidogrel in Relation to CYP2C19 Genotype Status. A Prospective, Randomized, 3-way Crossover PK/PD Study in Healthy Subjects

Clopidogrel pharmacogenetics: metabolism and drug interactions

The thienopyridine, clopidogrel bisulfate (clopidogrel), is the most widely prescribed antiplatelet therapy in the world. Clopidogrel, alone or in conjunction with aspirin as part of a dual antiplatelet therapy regimen, is the standard of care for reducing ischemic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke, or established peripheral artery disease. Initially approved for use in 1997, the label was updated by both the USA Food and Drug Administration and the European Medicines Agency in 2009 to include information regarding cytochrome P450 (CYP) genotype status and concomitant proton pump inhibitor use. Labeling warns of reduced effectiveness in those with impaired CYP2C19 function and to avoid concomitant clopidogrel use with drugs that are strong or moderate CYP2C19 inhibitors, such as omeprazole. The interpretation of this warning and the implementation in clinical practice is not without controversy. The following review provides a summary of the published evidence regarding CYP2C19 function, both genotype status and drug inhibition from concomitant proton pump inhibitors use, and response to clopidogrel.

Efficacy and tolerability of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole for the eradication of Helicobacter pylori infection and the effect of CYP2C19 genotype: A 1-week, randomized, open-label study in chinese adults

Background: First-line triple therapy with levofloxa- cin and amoxicillin plus a proton pump inhibitor has been reported to be effective and well tolerated in the eradication of Helicobacter pylori infection. Studies have reported that cytochrome P450 (CYP) 2C19 genotypes may affect the clinical efficacy of clarithromycinbased triple therapies, although there is only one report of such an effect with levofloxacin-based triple therapies. Objectives: This study evaluated the clinical efficacy and tolerability of a 1-week course of triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole as first-line treatment for H pylori infection in Chinese adults. It also investigated whether CYP2C19 genotype status affected rates of H pylori eradication with these regimens. Methods: Consecutive patients undergoing upper endoscopy at the First Affiliated Hospital of Nanjing Medical University between May 2008 and January 2009 were evaluated for inclusion. Eligible patients were those who tested positive for H pylori infection on biopsy-based testing (ie, histology and an in-house rapid urease test) or a validated 13C-urea breath test. Patients were randomized in an open-label fashion to receive levofloxacin 500 mg/d and amoxicillin 1000 mg BID plus either esomeprazole 20 mg BID (group A), esomeprazole 40 mg BID (group B), or rabeprazole 10 mg BID (group C) for 1 week. Patients were asked to record adverse events in a diary. Trained study assistants contacted patients by telephone within the first week after completion of therapy to collect data on drug compliance and adverse events. H pylori status was determined 4 weeks after the end of therapy using a 13C-urea breath test. Rates of H pylori eradication were calculated in the intent-to-treat (ITT) and per-protocol (PP) populations. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment-length polymorphism method. Results: Of 199 consecutive patients screened for eligibility, 184 H pylori-positive patients were enrolled in the study (61 in group A, 62 in group B, and 61 in group C). The overall sample was balanced in terms of age, sex, endoscopic diagnosis, and history of smoking. Rates of H pylori eradication in the ITT and PP populations were as follows: group A—85.2% (52/61) and 86.7% (52/60), respectively; group B—87.1% (54/62) and 90.0% (54/60); and group C—75.4% (46/61) and 75.4% (46/61). There were no significant differences in eradication rates among groups, nor were there any differences in rates of compliance (98.4%, 96.8%, and 100% in groups A, B, and C, respectively) or adverseevent profiles. Fifteen patients (7.6%) reported adverse events during the study (5 [8.2%] in group A, 6 [9.7%] in group B, and 4 [6.6%] in group C). The adverse events included diarrhea (6 patients), dizziness (5), abdominal pain (2), nausea (1), and skin rash (1). Three patients discontinued treatment because of adverse events ( 1 due to skin rash in group A and 2 due to dizziness in group B). In the 147 patients included in the PP analysis of the effect of CYP2C19 genotype, eradication rates were 88.9% (32/36) in poor metabolizers, 82.0% (50/61) in heterozygous extensive metabolizers, and 82.0% (41/50) in homozygous extensive metabolizers. Eradication rates did not differ significantly among genotype groups. Conclusions: One week of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole 20 or 40 mg BID or rabeprazole 10 mg BID was associated with H pylori eradication rates of 85.2%, 87.1%, and 75.4%, respectively, with no significant differences between treatment groups. There were no significant differences in eradication of H pylori by CYP2C19 genotype in this small population of Chinese adults.