Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions (original) (raw)
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Circulation: Cardiovascular Interventions, 2019
Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes du...
Impact of CYP3A4*1G Allele on Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel
European Journal of Drug Metabolism and Pharmacokinetics, 2016
Background and Objectives Resistance to the antiplatelet treatment with clopidogrel has both genetic and non-genetic causes. Polymorphic variants of cytochrome P450 3A4 isoenzyme involved in the bioactivation of clopidogrel might have an influence on responsiveness to the drug. The aim of this study was to evaluate the influence of CYP3A4*1G (IVS10?12G[A, rs2242480) on the pharmacokinetics and pharmacodynamics of clopidogrel. Methods CYP3A4*1G polymorphism was determined in a group of 82 patients undergoing percutaneous coronary intervention and taking 75 mg of clopidogrel daily. Concentrations of clopidogrel and its metabolites, inactive carboxylic acid derivative and two diastereoisomers of active thiol metabolite: H3 and H4, were determined by a validated HPLC-MS/MS method. Pharmacodynamic effect was measured by an impedance method with a Multiplate analyzer. Moreover, an effect of factors, such as CYP2C19 phenotype, age, gender, body mass index and interactions with drugs metabolized by CYP3A4 were also investigated. Results In the studied group allele frequencies were: wt-0.921, *1G-0.079. Pharmacokinetic parameters of clopidogrel and its metabolites were not significantly different in carriers of *1G allele, comparing to wt/wt homozygotes. Platelet aggregation was higher in heterozygotes than in wt/ wt carriers; however, the difference was not statistically significant (p = 0.484). In a multivariate analysis, which included age, body mass index, co-morbidities and coadministered drugs, CYP3A4*1G was not a predictor of values of H3 and H4 pharmacokinetic parameters and platelet aggregation. Conclusion CYP3A4*1G might not be a significant contributor to the variability in pharmacokinetic and pharmacodynamic response to clopidogrel therapy. Key Points No statistically significant differences in blood aggregation and pharmacokinetics of clopidogrel and its metabolites were found between CYP3A4*1G carriers and non-carriers.
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.
Clopidogrel Pharmacogenetics and Its Clinical Implications
American Journal of Therapeutics, 2010
Pharmacogenetics encompasses a range of phenomena ranging from pharmacology to therapeutics to toxicology and generally focuses on the study of genetic factors related to interindividual variability in drug response. Individual differences in the rate of platelet reactivity markedly influence normal hemostasis and the pathologic outcome of thrombosis. Response to clopidogrel varies widely, with nonresponse rates in various studies ranging from 4%-30% at 24 hours. Polymorphism involved in the response to antithrombotic drugs has been described in components of the hemostatic and thrombotic systems, and these include genetic variations. Polymorphisms in the hepatic enzymes involved in the metabolism of clopidogrel (e.g., CYP 1A2, CYP3A4, CYP2C19) or within the platelet membrane receptor (P2Y12) and/or polymorphism of platelet integrin a IIb b 3 or integrin a 2 b 1 may affect platelet responses and could influence response to clopidogrel administration. In this review, we discuss the pharmacogenetics of clopidogrel related to the phenomenon of response variability and its clinical implications.
The Journal of Clinical Pharmacology, 2014
An extensive investigation on pharmacokinetics of clopidogrel and its metabolites as well as pharmacodynamics of the drug was performed in patients with cardiovascular disease carrying various alleles coding CYP2C19 isoenzyme. The influence of non-genetic factors on the clopidogrel response was also studied. Plasma concentrations of clopidogrel, its carboxylic metabolite, and diastereoisomers of a thiol metabolite (the inactive H3 and the active H4) following an administration of 75 mg of the drug were determined in three groups of patients divided with respect to their CYP2C19 genotype: ultrametabolizers, extensive metabolizers, and intermediate metabolizers. The mean peak plasma concentration of H4 in intermediate metabolizers was 3.1-and 2.8-fold lower than that of ultrametabolizers (P ¼ 0.055) and extensive metabolizers (P ¼ 0.026), respectively. The mean H4 area under the curve (AUC 0-24 h) for intermediate metabolizers were significantly lower than that for ultrametabolizers (P ¼ 0.046). Intermediate metabolizers exhibited a significantly higher platelet aggregation than ultrametabolizers and extensive metabolizers (P ¼ 0.035). A multivariate analysis showed that the effect of CYP2C19*2 allele on an ADP-induced platelet aggregation was better pronounced in the presence of non-genetic risk factors (P ¼ 0.008). We concluded that the CYP2C19*2 genotype is the primary determinant of the antiplatelet response to clopidogrel therapy.
… of Thrombosis and …, 2007
Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y 12 adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. Objective: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. Methods: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). Results: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC 0-24 ; P = 0.004) and maximal plasma concentration (C max ; P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC 0-24 (P = 0.043), lower C max (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. Conclusions: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.
Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects
Journal of Thrombosis and Haemostasis, 2007
To cite this article: Fontana P, Hulot J-S, de Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007; 5: 2153-5. Clopidogrel, a prodrug, must be activated by hepatic cytochrome P450 (CYP) isoenzymes before being able to irreversibly block the platelet adenosine 5¢-diphosphate (ADP) receptor P2Y12 [1]. Clopidogrel responsiveness is highly variable among healthy subjects and patients, and a genetic variant (CYP2C19*2), which encodes a deficient version of the drug-metabolizing enzyme CYP2C19, has been associated with a markedly subnormal response to clopidogrel in 28 healthy subjects, based on the phosphorylation state of the vasodilatator phosphoprotein and platelet aggregation profile [2]. However, an intronic polymorphism (IVS10 + 12G > A) in the gene coding for another CYP isoform (CYP3A4) has also been recently linked to clopidogrel responsiveness based on the expression of activated glycoprotein (GP) IIb-IIIa but not based on the platelet aggregation profile . Both studies were small-scale and none has been replicated so far. This study was conducted to evaluate and quantify the genetic contribution of the CYP2C19*2 and CYP3A4 (IVS10 + 12A) alleles to the variability of clopidogrel responses in an unselected population of 94 healthy volunteers .
CYP2C19 or CYP3A5 Genotyping Does Not Predict Clinical Response to Clopidogrel
Journal of clinical pharmacology, 2018
Along with aspirin, clopidogrel has been a widely used antiplatelet therapeutic regimen. Although generally well tolerated, its efficacy varies among individuals, with the main hypothesis that its bioavailability relies on its bioconversion to the active compound, which, in turn, depends on the genetic background and/or interactions with other drugs. To determine which factors influenced response in our patients, 368 patients receiving combined antiaggregation therapy with aspirin and clopidogrel were followed for 1 year to record 30 novel cardiovascular acute events. This clinical relapse was considered a surrogate end point to measure therapeutic response under the influence of the CYP2C19*2, *3, and *17 and CYP3A5*3 alleles, as well as the effects of concomitant medication and the presence of known cardiovascular risk factors and comorbidity. We show that either single CYP2C19 or CYP3A5 genotyping or combined were not useful to predict clinical efficacy in this cohort. Rather tha...
Pharmacogenetics of Clopidogrel
Current Pharmaceutical Design, 2012
Clopidogrel used in conjunction with aspirin has a central role in the treatment of patients with an acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The pharmacokinetic and pharmacodynamic responses to this drug are highly variable leaving up to one third of patients with inadequate platelet inhibition or high on-treatment platelet reactivity (HPR), and subsequent increased ischemic cardiovascular events. Genetic variability in drug absorption and metabolism is a key factor responsible for the inefficient generation of the active drug metabolite. The two-step hepatic cytochrome P450 (CYP)-dependant oxidative metabolism of the prodrug appears to be of particular importance. Pharmacogenomic analyses have identified loss-of-function variant alleles of CYP 2C19 and specifically the 2C19*2 allele, to be the predominant genetic mediators of the antiplatelet effect of clopidogrel. Carriers were have been shown to have lower active metabolite levels of clopidogrel, higher platelet reactivity and associated poorer outcomes. Rapid and accurate point-of-care genetic tests to identify these alleles are currently in development but several questions about the role of such testing remain such as patient selection and whether personalized treatment based on genotype has a positive impact on clinical outcome. At present, genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data. However, the significant body of research published to date suggests a likely role when used in combination with platelet function analysis in ACS patients undergoing stenting who have other known risk factors for recurrent ischemic events.