Clopidogrel Pharmacogenetics

Study of genetic variability that causes individual responses to clopidogrel


Tailor clopidogrel dosage according to each person genetic background.

 

Did you know that clopidogrel…

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 Is still used worldwide as an antiplatelet agent in the treatment and prevention of atherothrombotic events?

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Inhibits platelet aggregation, affecting platelets irreversibly for the remainder of their lifespan?

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If not properly metabolized, may cause severe adverse cardiovascular effects?

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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].


International Guidelines 

Screen Shot 2015-06-10 at 16.47.38The 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 [5].

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 [8].

– Plavix (clopidogrel bisulfate) 75 mg tablets: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) [5]

– Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update [8]

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:

CYP2C19 Haplotype CYP2C19 phenotype Degree of platelet inhibition
*1/*17; *17/*17 Ultrarapid metabolizer Increased
*1/*1 Extensive metabolizer Normal
*1/*2; *1/*3; *2/*17 Intermediate metabolizer Reduced
*2/*2; *2/*3; *3/*3 Poor metabolizer Significantly reduced

Adapted from [8].

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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].


Clopidogrel Genetic Testing is indicated for:

icon-check-trombogene Individuals starting clopidogrel therapy;

icon-check-trombogene  Individuals already taking clopidogrel but experiencing adverse drug reactions;

icon-check-trombogene  Individuals with family history of adverse reactions to clopidogrel.



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.


 

 

Start improving Clopidogrel administration today

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