Cytochrome P450 2C19 Poor Metabolizers Research Articles

CYP2C19 Loss-of-Function is an Associated Risk Factor for Premature Coronary Artery Disease: A Case-Control Study.

Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship. This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed. A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) phenotypes, respectively. CYP2C19 *2/*2 genotype frequency was higher, *1/*1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥24.0 kg/m2 (≥24.0 kg/m2 vs 18.5-23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041-1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283-3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044-1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054-1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200-2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077-1.740, p = 0.010) were associated with PCAD. CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.

CYP2C19 Poor Metabolizer Status and High System Inflammation Response Index are Independent Risk Factors for Premature Myocardial Infarction: A Hospital-Based Retrospective Study.

Atherosclerosis (AS) is a sustained chronic vascular inflammatory response caused by lipid metabolism disorders and immune response disorders and is the main cause of premature (men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). Cytochrome P450 2C19 (CYP2C19) (related to vascular function and lipid metabolism) and peripheral immune cell levels and plays an important role in the course of AS. The association CYP2C19 polymorphisms, comprehensive immunoinflammatory indices with PMI susceptibility is unclear. This study included 485 PMI patients, and 639 age-matched non-PMI individuals as controls, from January 2019 to March 2024. The relationship between CYP2C19 polymorphisms, peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) and PMI risk were analyzed. The inflammatory indices levels in PMI patients were higher than those in controls (all p<0.05). The frequencies of the CYP2C19 *1/*2 and *2/*2 genotypes were higher, while the frequency of the *1/*1 genotype was lower in the PMI patients than those in controls. The cut-off values of TC, TG, LDL-C, PIV, SII, and SIRI were 5.065, 1.305, 2.805, 410.485, 869.645, and 1.495 for distinguishing PMI, respectively. Logistic regression analysis showed that male (odds ratio (OR): 1.607, 95% confidence interval (CI): 1.134-2.277, p=0.008), history of smoking (OR: 7.108, 95% CI: 4.351-11.614, p<0.001), diabetes mellitus (OR: 4.906, 95% CI: 3.333-7.223, p<0.001), CYP2C19 poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) (OR: 2.147, 95% CI: 1.279-3.603, p=0.004), and high TG (≥1.305 vs <1.305, OR: 2.598, 95% CI: 1.864-3.623, p<0.001) and SIRI level (≥1.495 vs <1.495, OR: 2.495, 95% CI: 1.432-4.349, p=0.001) were independent risk factors for PMI. CYP2C19 PM phenotype, high SIRI level (≥1.495) and TG level (≥1.305), male, history of smoking, and diabetes mellitus were independently associated with PMI susceptibility.

CYP2C19 Genotype Is Associated With Adverse Cardiovascular Outcomes in Black Patients Treated With Clopidogrel Undergoing Percutaneous Coronary Intervention.

Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

Relationships of Proton Pump Inhibitor-Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study.

Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non-PM group (hazard ratio for PM vs. non-PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non-PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.

CYP2C19 Loss-of-function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes.

Sulfonylureas (SUs) are predominantly metabolized by cytochrome p450 2C9 (CYP2C9) and cytochrome p450 2C19 (CYP2C19) enzymes. CYP2C9 polymorphisms are associated with greater treatment response and hypoglycemic risk in SU users. However, there are no large scale pharmacogenetic studies investigating the effect of loss‐of‐function alleles CYP2C19*2 and CYP2C19*3, which occur frequently in East Asians. Retrospective pharmacogenetic analysis was performed in 11,495 genotyped patients who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017, with follow‐up to December 31, 2019. The associations of CYP2C19 polymorphisms with SU treatment failure, early HbA1c response, and severe hypoglycemia were analyzed by Cox regression or logistic regression assuming an additive genetic model. There were 2341 incident SU users that were identified (mean age 59 years, median diabetes duration 9 years), of which 324 were CYP2C19 poor metabolizers (CYP2C19 *2/*2 or *2/*3 or *3/*3). CYP2C19 poor metabolizers had lower risk of SU treatment failure (hazard ratio 0.83, 95% confidence interval (CI) 0.72–0.97, P = 0.018) and were more likely to reach the HbA1c treatment target < 7% (odds ratio 1.52, 95% CI 1.02–2.27, P = 0.039) than wild‐type carriers (CYP2C19 *1/*1) following adjustment for multiple covariates. There were no significant differences in severe hypoglycemia rates among different CYP2C19 genotype groups. CYP2C19 polymorphisms should be considered during personalization of SU therapy.

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

Since the approval of the first proton pump inhibitor (PPI) in 1989, our knowledge regarding this class of medications has further developed. An increasing amount of data now supports the association between cytochrome P450 2C19 (CYP2C19) phenotype and PPI safety and efficacy. This includes pediatric studies, such as those published here and in other pediatric journals within the past year. Moreover, the most recent pediatric Helicobacter pylori guidelines stated that using the PPIs that are less dependent on CYP2C19 for inactivation may be preferred for H pylori eradication among populations that are more likely to have rapid clearance of CYP2C19-metabolized PPIs. Conversely, pantoprazole package insert recommends a dose reduction in known pediatric CYP2C19 poor metabolizers (PMs), citing a 6-fold increase in serum concentrations compared with normal metabolizers (NMs). The purpose of this communication is to introduce a recently published Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and PPI dosing.

CYP2C19 polymorphism has no correlation with the efficacy and safety of thalidomide in the treatment of immune-related bowel disease.

To explore the relationship between hepatic cytochrome P450 2C19 (CYP2C19) gene polymorphisms and the effectiveness and safety of thalidomide in the treatment of patients with immune-related bowel disease (IRBD). CYP2C19 variants in 79 patients treated with thalidomide were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The clinical response and adverse events of the thalidomide treatment were recorded. The potential influences of the CYP2C19 genotype polymorphisms on the clinical efficacy and adverse events of thalidomide were then investigated. Altogether 79 patients with IRBD (70 with Crohn's disease, three with ulcerative colitis and six with Behcet's disease) receiving thalidomide therapy were recruited from January 2013 to February 2015 in a tertiary IBD center in China. Overall, 21.5% (17/79) of these patients had CYP2C19 poor metabolizers genotype (PM). The overall response rate and the incidence of adverse events of CYP2C19 extensive metabolizers genotype were not significantly different from that of the PM when IRBD patients were treated with thalidomide (P = 0.517 and 0.816, respectively). CYP2C19 polymorphisms do not seem to be associated with efficacy of thalidomide and the incidence of adverse events in treating IRBD.

Investigating CYP2C19 loss-of-function allele statuses and their association with stroke of different etiologies in a Taiwanese population.

CYP2C19 loss-of-function single-nucleotide polymorphisms (SNPs) are associated with poor responses of clopidogrel in secondary prevention of ischemic stroke (IS). It is still unclear whether these SNPs, which may result in poor cytochrome P450 2C19 (CYP2C19) enzymatic activity, affect the occurrence of IS and its subtypes. The present study evaluated the relationship between the CYP2C19 loss-of-function alleles and IS. Eight hundred sixty-eight patients with IS and 557 nonstroke (NS) control individuals were prospectively recruited. Stroke etiologies, including large-artery atherosclerosis (LAA), cardioembolism (CE), and small-vessel occlusion (SVO), were determined. The two most common CYP2C19 loss-of-function alleles worldwide, CYP2C19*2 and CYP2C19*3, were investigated by genotyping. Patients with two loss-of-function alleles of the CYP2C19 genes were classified as poor metabolizers. Our population has a high frequency of CYP2C19 loss-of-function alleles, mostly contributed by CYP2C19*2, being present in 51.3% to 57.5% of patients with IS of different etiologies and 53.1% of NS individuals. The proportions of CYP2C19 poor metabolizers within NS group and each IS group with disparate etiology are similar (NS 73 [13.1%]; LAA 44 [14.2%], p = 0.623; CE 26 [14.0%], p = 0.541; SVO 38 [13.3%], p = 0.443). Nevertheless, the frequencies of CYP2C19*3 allele were different among the NS and different IS subgroups. Multivariate analyses adjusting for age, sex, and vascular risk factors revealed that CYP2C19*3 allele was a protective factor for SVO (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.3 to 0.9, p = 0.015 [vs NS], OR = 0.5, 95% CI = 0.3 to 0.8, p = 0.010 [vs LAA and CE]). The CYP2C19 poor metabolizer is not associated with IS and its subtypes. Furthermore, CYP2C19*3 may be a protective factor for SVO and its mechanism warrants further investigation.

CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharmacokinetic Modeling Study.

Objective: Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs) that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth. Using pharmacokinetic (PK) models in adolescents, we sought to (1) model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under curve, AUC) and maximum concentration (Cmax), (2) evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and Cmax, and (3) determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents. Methods: Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data for escitalopram and sertraline, we modeled exposure (AUC0-24) and Cmax and determined CYP2C19-guided dosing strategies. Results: Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline, Cmax and AUC0-24 were higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline. For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC0-24 and Cmax similar to NMs receiving 150 mg/day, PMs require 100 mg/day, whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs. Conclusions: This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations could require dose adjustments in CYP2C19 poor metabolizers and UMs, although the magnitude of these differences were more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.

Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications.

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance.Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003–2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups.Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01).Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19 *2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE.

Sex differences in the effect of cytochrome P450 2C19 polymorphisms on the risk of diabetic retinopathy

Cytochrome P450 2C19 (CYP2C19) is expressed in human endothelial cells and catalyzes the biosynthesis of vasoprotective epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic acid from arachidonic acid. This study investigated the association between CYP2C19 polymorphisms and an increased risk of diabetic retinopathy (DR). A clinic-based retrospective longitudinal analysis was carried out that included 383 Japanese patients with type 2 diabetes mellitus. Compared with male extensive metabolizers, female intermediate metabolizers [adjusted odds ratio (OR), 2.43; 95% confidence interval (95% CI), 1.17-5.06] and poor metabolizers (OR, 7.49; 95% CI, 2.64-21.26) were at a significantly higher risk of developing DR. Furthermore, the CYP2C19 poor metabolizer genotype was found to be an independent risk factor for DR only in women when patients were stratified by sex (OR, 4.18; 95% CI, 1.42-12.26). This is the first report showing the interactive effect of sex and CYP2C19 polymorphisms on microvascular disease in humans, although further investigations are needed to verify these findings.

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥ 24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.

Markedly Reduced Overall Survival of CYP2C19 *2/*2 Homozygotes After Myeloablative Hematopoietic Stem Cell Transplantation

AbstractAbstract 520Patients with allelic variations of cytochrome P450 enzymes that affect drug metabolism have been shown to have worse outcomes after hematopoietic stem cell transplantation (HSCT). One study demonstrated higher treatment-related mortality in carriers of the cytochrome P450 2C19 (CYP2C19) loss-of-function allele, *2, however the underlying cause remains unclear. Extensive metabolizers (EM) have two wild-type alleles of CYP2C19 (i.e., *1/*1), while intermediate metabolizers (IM) and poor metabolizers (PM) are heterozygous or homozygous for common allelic variants of CYP2C19 that produce null mutations (i.e., *1/*2, *1/*3 for IM and *2/*2, *2/*3 and *3/*3 for PM). We hypothesized that allelic variations in CYP2C19 may lead to worse outcomes after HSCT due to altered metabolism of CYP2C19 substrates or other drugs commonly given to patients receiving HSCT. We analyzed DNA samples from 344 patients who received high-dose CPA conditioning and total body irradiation prior to allogeneic HSCT between 2002 and 2008. Genotyping was performed to detect the *1,*2 and *3 allelic variants of CYP2C19. Non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) were determined for EM, IM and PM. We collected kidney and liver function test results and recorded all medications in the PM group. The EM, IM and PM phenotype was found in 249 (72.4%), 83 (24.1%) and 12 (3.5%) patients, respectively. CYP2C19 PM had significantly worse overall survival (3-yr: 25%) than EM and IM (55%) (Figure, adjusted HR=2.78, p=0.004). PFS was also significantly worse in PM (3-yr: 25%) versus EM and IM (53%) (adjusted HR=2.38, p=0.008). No significant difference in NRM and relapse was seen (p=0.10 and p=0.42, respectively). Compared to the three surviving patients, the nine PM who died had higher maximum post-transplant concentrations of creatinine (2.59 ± 2.33 mg/dl vs. 1.37 ± 0.06 mg/dl), total bilirubin (16.7 ± 18.4 mg/dl vs. 1.5 ± 0.8 mg/dl), AST (310 ± 144 U/l vs. 156 ± 107 U/l), and alkaline phosphatase (787 ± 811 U/l vs. 207 ± 84 U/l). A total of 192 different medications were administered to the twelve PM. Of the drugs metabolized by CYP2C19, seven of the nine patients who died received voriconazole and four received omeprazole. None of the three surviving patients received either drug. The significantly worse overall survival in CYP2C19 *2 homozygotes who carry two non-functional alleles may have multiple causes, one of them being administration of triazole drugs, in particular voriconazole. Voriconazole is an effective antifungal commonly given to patients after HSCT. It undergoes extensive hepatic metabolism, primarily by CYP2C19. PM have significantly higher concentrations of voriconazole than EM and IM, which may not only lead to direct voriconazole toxicity but also to exacerbated drug-drug interactions and altered concentrations of immunosuppressants and antibiotics. Since more than a thousand patients who receive HSCT each year are homozygous for CYP2C19 *2, further investigation into the causes of poor outcomes in this patient subset is warranted. In the interim, we propose testing for the CYP2C19 *2 allele in patients undergoing HSCT and careful monitoring of drug levels in the homozygotes, in particular voriconazole and immunosuppressants.Overall survival by CYP2C19 Genotype. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A genetic polymorphism of CYP2C19 is associated with susceptibility to biliary tract cancer

Cytochrome P450 2C19 (CYP2C19) is clinically important for the metabolism of many therapeutic drugs. CYP2C19 has two main point mutation sites leading to low metabolic capacity. Several CYP enzymes are also important for the metabolism of chemical carcinogens, and several studies have reported associations between CYP polymorphism and cancer susceptibility. Speculating on a potential association between CYP2C19 polymorphism and cancer susceptibility, we conducted this study in two phases. Cell lines of various gastroenterological cancers were screened in the first phase. A clinical investigation was then conducted to confirm the association with the candidate cancer in the second phase. Genetic polymorphism of CYP2C19 was investigated in a total of 114 cell lines of five gastroenterological cancers. Based on this screening investigation suggesting an association with biliary tract cancer, we conducted a related study by recruiting 65 patients with biliary tract cancer and 566 patients with benign diseases as controls. Among the 114 cell lines investigated, biliary tract cancer was suggested to be most strongly associated with poor metabolizers of CYP2C19. Among 65 patients with biliary tract cancer, 18 (28%) were poor metabolizers of CYP2C19, whereas 87 (15%) of 566 control patients were poor metabolizers. The age- and gender-adjusted odds ratios for intermediate and poor metabolizers regarding the risk of biliary tract cancer were 1.5 (95% CI: 0.8-3.0, P=0.17) and 2.7 (1.3-5.9, P=0.006) compared to extensive metabolizers. A genetic polymorphism of CYP2C19 is associated with susceptibility to biliary tract cancer.

Influence of CYP2C19 and ABCB1 polymorphisms on plasma concentrations of lansoprazole enantiomers after enteral administration

An intraoral annihilation enteric-coated preparation of lansoprazole is often administered via intestinal fistula. The purpose of this study was to determine the plasma concentrations of lansoprazole enantiomers after enteral administration in subjects with cytochrome P4502C19 (CYP2C19) and ABCB1 C3435T genotypes.Fifty-one patients who underwent a curative oesophagectomy for oesophageal cancer were enrolled in this study. After a single enteral dose of racemic lansoprazole (30 mg), plasma concentrations of lansoprazole enantiomers were measured 4 h post-dose (C4h).There were significant differences in the C4h of (R)- and (S)-lansoprazole and the R/S-enantiomer ratio for three CYP2C19 genotype groups (*1/*1, *1/*2 ± *1/*3, and *2/*2 ± *2/*3 ± *3/*3 (poor metabolizers (PMs)), but not the ABCB1 C3435T genotypes. In a stepwise forward selection multiple regression analysis, the C4h of (R)- and (S)-lansoprazole were associated with CYP2C19 PMs (p = 0.0005 and < 0.0001 respectively) and age (p = 0.0040 and 0.0121 respectively), while the R/S-enantiomer ratio was associated with CYP2C19*1/*1 (p = 0.0191) and CYP2C19 PMs (p = 0.0426).Direct administration to the jejunum is unaffected by residence time in the stomach and the gastric emptying rate. With enteral administration, CYP2C19 phenotyping of patients using the lansoprazole R/S enantiomer index at C4h could be possible.

Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD)

The pharmacokinetic profile of pantoprazole granules was assessed in neonates and preterm infants with gastroesophageal reflux disease (GERD) in a multicenter, randomized, open-label trial. Patients were randomly assigned to either the pantoprazole 1.25 mg (approx. 0.6 mg/kg) or 2.5 mg (approx. 1.2-mg/kg) group and treated for > or =5 consecutive days. Blood was sampled either at 0, 2, 8, and 18 h postdose or at 0, 1, 4, and 12 h postdose on day 1 and at 3 and 6 h postdose after > or =5 consecutive doses. Cytochrome P450 2C19 (CYP2C19) and CYP3A4 genotypes were determined. Safety was monitored. Population pharmacokinetics (popPK) analyses were conducted using nonlinear mixed-effects modeling. The popPK modeling of the pantoprazole 1.25 mg and 2.5 mg groups obtained mean (+/-standard deviation) estimates for the area under the plasma concentration versus time curve (AUC) of 3.54 (+/-2.82) and 7.27 (+/-5.30) microg h/mL, respectively, and mean estimates for half-life of 3.1 (+/-1.5) and 2.7 (+/-1.1) h, respectively. Pantoprazole did not accumulate following multiple-dose administration. The two patients with the CYP2C19 poor metabolizer genotype had a substantially higher AUC than extensive metabolizers. No safety-related discontinuations occurred. In preterm infants and neonates, pantoprazole granules were generally well tolerated, mean exposures with pantoprazole 2.5 mg were slightly higher than that in adults who received 40 mg. While the half-life was longer, accumulation did not occur.

Poor metabolizer genotype status of CYP2C19 is a risk factor for developing gastric cancer in Japanese patients with Helicobacter pylori infection

Cytochrome P450 2C19 (CYP2C19) polymorphism has been associated with the development of lung, liver or oesophageal cancer by detoxification of carcinogen(s) or activation of procarcinogen(s). To clarify the association between CYP2C19 polymorphisms and gastric cancer development in Japanese. Methods : We determined CYP2C19 genotypes (CYP2C19*1, *2 and *3) in 111 Helicobacter pylori-positive patients with gastric cancer and 315 H. pylori-positive controls without gastric cancer consisting of patients with gastritis only or peptic ulcer. Frequencies of CYP2C19 genotypes and serum pepsinogen I and II levels, a biomarker of gastric atrophy, in the gastric cancers and controls were compared. Frequencies of homozygous extensive metabolizers, heterozygous extensive metabolizers and poor metabolizers were 31.5%, 42.3% and 26.2% in the gastric cancers and 38.1%, 47.0% and 14.9% in the controls, respectively (P = 0.046). Poor metabolizers were associated with an increased risk for developing gastric cancer with the age- and sex-adjusted odds ratio (OR) of 1.975 [95% confidence interval (CI): 1.068-3.649], especially for diffuse type (OR: 3.385, CI: 1.187-9.648). There is no significant association between CYP2C19 genotypes and serum pepsinogen I level or pepsinogen I/II ratios, although serum pepsinogen I level in gastric cancers were significantly decreased. In H. pylori-positive Japanese, poor metabolizers of CYP2C19 appear to be at an increased risk for developing gastric cancer, especially diffuse type, and may require an intensive follow-up for scrutinizing possible gastric cancer development.