Study of genetic variability that causes individual responses to clopidogrel
Tailor clopidogrel dosage according to each person genetic background.
Did you know that clopidogrel…
Is still used worldwide as an antiplatelet agent in the treatment and prevention of atherothrombotic events?
Inhibits platelet aggregation, affecting platelets irreversibly for the remainder of their lifespan?
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Why Clopidogrel pharmacogenetics matter?
According to the FDA [1,5], Clopidogrel pharmacogenetics can play an important role in:
1. Drug exposure and clinical response variability
2. Defining the risk for adverse cardiovascular events platelet aggregation associated with clopidogrel therapeutics
3. Genotype-specific dosing or defining alternative anti platelet therapy
Clopidogrel Administration Issues
Being a prodrug, clopidogrel needs hepatic bioactivation into an active form (Clop-AM) in order to inhibit platelet aggregation. CYP2C19 is an important hepatic drug-metabolizing enzyme and is responsible for the metabolic activation of clopidogrel. It is well established that clopidogrel’s metabolic activation can be impaired by genetic variants in CYP2C19 gene and by concomitant medications that interfere with CYP2C19 action [2,3,5-7].
The clinical importance of CYP2C19 genotype affecting clopidogrel pharmacokinetics and pharmacodynamics has been extensively studied in the recent years. CYP2C19 genetic polymorphisms have been shown to impair the metabolism of this antiplatelet drug. Loss-of-function polymorphisms affect the degree of platelet inhibition by decreasing Clop-AM levels, resulting in an increased risk of recurrence of major adverse cardiovascular events. Conversely, gain-of-function alleles are associated with increased risk of bleeding [4,6-8].
The FDA issued a Boxed Warning about patients who do not effectively metabolize clopidogrel and therefore may not receive the full benefits of the drug. It is recommended that health care professionals consider the use of other antiplatelet medications or alternative dosing strategies for clopidogrel. It was also stated that CYP2C19 genetic testing could be useful to optimize drug therapy .
Also, the Clinical Pharmacogenetics Implementation Consortium (CPIC), that develops peer-reviewed gene–drug guidelines that are published and updated periodically based on new developments in the field, has established several therapeutic recommendations regarding CYP2C19 phenotype .
– Plavix (clopidogrel bisulfate) 75 mg tablets: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) 
– Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update 
Clopidogrel Pharmacogenetics Testing
Evaluation of the genotypes that affect Clopidogrel metabolism.
What is evaluated in this test?
The test evaluates 3 genetic variants in CYP2C19 gene associated with clopidogrel’s pharmacokinetics and pharmacodynamics, whose combination produce 9 haplotypes related to the level of clopidogrel’s metabolization.
Polymorphisms within CYP2C19 gene can either increase (gain-of-function alleles) or decrease (loss-of-function alleles) the catalytic activity of the encoded enzyme, resulting in four possible phenotypes that affect clopidogrel metabolism and consequent platelet inhibition as follows:
Adapted from .
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Disclaimer: It should always be kept in mind that the results of genetic testing should be interpreted in the context of the patient’s medical evaluation, family history and racial/ethnic background. Other factors, such as age, body mass index, diabetes mellitus and the use of certain proton pump inhibitors (such as omeprazole) are also known to influence clopidogrel response [5,8].
As an antiplatelet agent, clopidogrel is advised, when aspirin is contraindicated, in patients with peripheral arterial disease, history of coronary artery bypass surgery or with known cardiovascular disease. The dual therapy with aspirin is indicated in percutaneous angioplasty with stenting, in acute coronary syndromes without stenting, in cases of atrial fibrillation where oral anticoagulants cannot be given, and in patients with known cardiovascular disease [2-4].
2. Clopidogrel Metabolism
Cytochrome P450 enzymes, which are found at high levels at the liver, metabolize numerous drugs.
Loss-of-function alleles *2 and *3: Cause an impaired antiplatelet effect in clopidogrel-treated patients, resulting in an increased risk of the recurrence of major adverse cardiovascular events [4,6-8].
Wild-type allele *1: The *1 allele denotes the wildtype and is considered to produce an enzyme with normal function levels .
Gain-of-function allele *17: Is associated with increased risk of bleeding. The currently available evidence indicates that *17 allele is unable to completely compensate the loss-of-function alleles [6,8,9].
The frequency of these alleles differs across populations, and among the Europeans *17 is the most prevalent (21%), followed by *2 (15%) and *3 (0.42%) [6,8].
Poor clopidogrel metabolizers: Have significant reduction in platelet inhibition, therefore have an increased risk of adverse cardiovascular events.
Ultra-rapid clopidogrel metabolizers: Have increased platelet inhibition, therefore may have an increased risk of bleeding.
-  Food and Drug Administration webpage: http://www.fda.gov/
-  JAMA. 2011. 306(24):2704-14. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis.
-  Mol Biol Rep. 2011. 38(3):1697-702. Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel.
-  Circulation. 2010. 121(4):512-8. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.
-  http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s048lbl.pdf
-  J Thromb Haemost. 2012. 10(2):199-206. The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients.
-  JAMA. 2010. 304(16):1821-30. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
-  Clin Pharmacol Ther. 2013. 94(3):317-23. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update.
-  Clin Pharmacol Ther. 2012. 92(4):414-7. Pharmacogenomics knowledge for personalized medicine.
- Circulation. 2008. 117(2):261-95. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee.
- Cardiovasc Hematol Disord Drug Targets. 2014. 14(3):225-30. Recent developments in antiplatelet therapy after percutaneus coronary intervention.
- Am Heart J. 2014. 168(1):16-22.e1. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study.
- N Engl J Med. 2009. 360(4):354-62. Cytochrome p-450 polymorphisms and response to clopidogrel.
- J Am Coll Cardiol. 2007. 49(14):1505-16. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.
Clopidogrel Genetic Testing is indicated for:
Providing an adequate antithrombotic therapy is important to prevent blood clots.
Reducing the adverse drug reactions by prescribing the most adequate clopidogrel dose may prevent serious or life-threatening events.