CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients (original) (raw)
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Basic & clinical pharmacology & toxicology, 2017
Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12 assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clop...
Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was selfdefined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.
European Journal of Clinical Pharmacology, 2018
Purpose Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM). Methods We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP. Results We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759). Conclusions Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals. Trial registration Clinical Trials.gov NCT03373552 (Registered
Pharmacogenomics, 2012
Pharmacogenomics (2012) 13(5), 1-xxx ReseaRch aRticle CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects Clopidogrel, a platelet P2Y 12 receptor inhibitor, is universally administered to patients with acute myocardial infarction and to patients undergoing percutaneous coronary intervention (PCI) because of its proven efficacy in reducing major adverse cardiovascular events in these populations [1,2]. Although newer P2Y 12 inhibitors are now commercially available, clopidogrel, driven by extensive clinical data and the recent availability of generic clopidogrel, is currently the dominant compound in clinical use.
Clopidogrel Response in Acute Coronary Syndrome Patients with CYP2Y12*2 and CYP2Y12*3 Polymorphisms
Russian Journal of Cardiology, 2018
Ischemic heart disease is the leading cause of death and disability in the world with a fairly high portion coming from low and middle-income countries (LMICs). Deaths due to ischemic heart disease and acute coronary syndrome (ACS) appear at a younger age in LMICs countries compared with high-income countries, often occurring during the productive years [1]. Data from the Jakarta Cardiovascular Study in 2008 at the Heart Hospital Harapan Kita shows the prevalence of myocardial infarction at 5,29%-4,12% and 7,6% in women and men, respectively. Over the past seven years, the prevalence of myocardial infarction has increased by 4,09% or an average of 0,6% per year [2]. Clopidogrel is an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor, which is the standard drug therapy in the management of ACSs and in patients who will be undergoing percutaneous coronary intervention (PCI) [3-5].
Lancet, 2009
Background Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel.
Role of CYP2C19 genotype testing in clinical use of clopidogrel: is it really useful?
Expert Review of Cardiovascular Therapy, 2018
Introduction: P2Y12 inhibitors, including clopidogrel have become an integral part of treatment for patients receiving coronary stent placement as a result of stable coronary artery disease or acute coronary syndromes (ACS) and also for medically managed ACS patients. Areas covered: Clopidogrel efficacy can be significantly modified by polymorphism of CYP2C19 genotype (more than 25 allelic variants) involved in its metabolism that can adversely affect its anti-platelet activity. As a result, a substantial number of patients (20-30%) with ACS show an inadequate response to clopidogrel despite a standardized dosing regimen. Experts commentary: Currently, there is conflicting evidence in regards to the use of CYP2C19 genotyping to identify poor responders to clopidogrel in clinical practice. ACC/AHA guidelines do not recommend routine use of CYP2C19 in clinical practice, whereas Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend its use to identify poor/intermediate metabolizers of Clopidogrel and suggest alternative P2Y12 inhibitors among ACS patients undergoing percutaneous coronary intervention. This review article will look at the literature evidence for the use of CYP2C19 genotyping in clinical practice.
European heart …, 2009
The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Methods and results Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilatorstimulated phosphoprotein (VASP) and VerifyNow TM P2Y12 were measured predose, 2, and 24 + 4 h post-LD and predose during the MD period on Day 14 + 3 and Day 29 + 3. For clopidogrel, active metabolite exposure was significantly lower (P ¼ 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow TM P2Y 12 reaction unit (PRU) values were significantly higher (P , 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Conclusion Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y 12 inhibition, but has no significant influence on the response to prasugrel.
Pharmacology, 2013
Background/Aims: The study was conducted to assess the influence of CYP2C19 polymorphisms on clopidogrel response variability and recurrent cardiovascular (CV) events in Chinese patients undergoing percutaneous coronary intervention (PCI). Methods: Platelet aggregation induced by 5 and 20 µmol/l adenosine diphosphate was measured in 109 patients at baseline, 12 h and 36 h after loading with 300 mg of clopidogrel. The primary end point was recurrent CV events, and the follow-up was scheduled at 1, 3, 6 and 12 months after PCI. The polymorphisms of CYP2C19*2 and CYP2C19*3 were genotyped by DNA sequencing analysis. Results: The maximal aggregation rates and inhibition of platelet aggregation among CYP2C19*1/*1, CYP2C19*1/*2 or *3 and CYP2C19*2/*2 or *3 genotypes were significantly different at 12 and 36 h after clopidogrel loading dose administration. Multiple linear regression analysis demonstrated that CYP2C19*2 and CYP2C19*3 might be predictors of clopidogrel response variability. D...