New Clopidogrel Pharmacogenetics Testing

The antiplatelet agent clopidogrel is extensively used worldwide, being indicated in the treatment or prevention of atherothrombotic events. Clopidogrel is a prodrug that is converted by liver cytochrome P450 (CYP) enzymes into its bioactive form, Clop-AM. This metabolite selectively inhibits the binding of adenosine diphosphate to its platelet receptor, thereby inhibiting platelet aggregation.

CYP2C19 is an important hepatic drug-metabolizing enzyme and is responsible for the metabolic activation of clopidogrel. It is well established that the metabolism of clopidogrel to its active metabolite can be impaired by genetic variants in CYP2C19 and by concomitant medications that interfere with CYP2C19. 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 the recurrence of major adverse cardiovascular events. Conversely, gain-of-function alleles are associated with increased risk of bleeding.

In this context, the Food and Drug Administration (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 stated that CYP2C19 genetic testing could be useful to optimize drug therapy. Also, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has established several therapeutic recommendations regarding CYP2C19 phenotype.

INDICATION FOR CLOPIDOGREL PHARMACOGENETIC TESTING

• For individuals starting clopidogrel therapy
• For individuals already taking clopidogrel but experiencing adverse drug reactions
• For individuals with family history of adverse reactions to clopidogrel

WHAT IS EVALUATED IN THE HEARTGENETICS PHARMACOGENETIC TESTING?

HeartGenetics tests 3 genetic variants related to 9 haplotypes of CYP2C19

Cytochrome P450 (CYP) enzymes, which are found at high levels in the liver, have oxygenase activity and metabolize numerous drugs. 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:

BENEFITS OF GENETIC TESTING

The study of clopidogrel pharmacogenetics:

• Define the risk of adverse cardiovascular events and platelet aggregation associated with CLP therapeutics
• Define the optimal dose therapy or recommends for an alternative antiplatelet therapy (if no contraindication)

Providing an adequate antithrombotic therapy is important to prevent blood clots.

Clopidogrel is advised when aspirin is contraindicated, in peripheral arterial disease, in patients with history of coronary artery bypass surgery and in patients with known cardiovascular disease. Moreover, the dual therapy with aspirin is indicated in percutaneous angioplasty with stenting, in acute coronary syndromes without stenting, in atrial fibrillation in cases where oral anticoagulants cannot be given, and in patients with known cardiovascular disease.

Reducing the ADR by prescribing the most adequate clopidogrel dose may prevent serious or life-threatening events.

Observations: The results of the genetic testing should be interpreted in the context of the patient’s medical evaluation, family history and racial/ethnic background.

REQUEST A CLOPIDOGREL PHARMACOGENETICS TEST

REFERENCES

– Journal of Thrombosis and Haemostasis 10, 199 (2012).
– U. Food, D. Administration, et al. , Accessed March 19 (2010).
– Molecular biology reports 38, 1697 (2011).
– New England Journal of Medicine 360, 354 (2009).
– Pharmacology & Therapeutics 94, 317 (2013).
– Circulation 121, 512 (2010).
– Jama 304, 1821 (2010).