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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines: Clopidogrel Therapy and the CYP2C19 Genotype

What are the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines?

In the era of personalized medicine, we are witnessing genetic tests being incorporated into routine clinical practices. However, the extent to which pharmacogenomic tests have been qq adopted has been low, majorly due to the lack of a coherent and curated set of guidelines for their practice.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed certain guidelines that have been endorsed by several medical societies.They are designed to assist clinicians on how to use the results from genetic tests to determine the course of drug therapy for each patient. Genotype-based drug guidelines will help clinicians understand how a patient of a specific genotype would respond to or metabolize a particular drug. This will enable them to evaluate subsequent therapeutic options and to determine the dosage strength.

The Drug: Clopidogrel

Clopidogrel is a prodrug and broken down in the liver. It belongs to a drug class known as platelet inhibitors and is used in antiplatelet therapy. It essentially inhibits platelet aggregation to prevent the formation of blood clots. It is administered along with drugs like aspirin to patients suffering from coronary heart disease, Acute Coronary Syndrome (ACS) and for patients undergoing Percutaneous Coronary Interventions (PCI). However, in many patients, insufficient clopidogrel-induced platelet inhibition may lead to myocardial infarction (MI), stroke, thrombosis or death.

Clopidogrel is a prodrug in its inactive form that undergoes biotransformation in the liver to form an active metabolite that inhibits the platelet ADP receptor P2RY12 receptor in a selective and irreversible manner. This inhibits the platelet aggregation process for its lifespan (of around ten days)

About 85% of the clopidogrel prodrug undergoes hydrolysis by esterases into inactive forms. This leaves only 15% of the prodrug for the biotransformation in the active drug. Several Cytochrome P450 enzymes are involved in the sequential oxidation of clopidogrel to its active form.

The Gene: CYP2C19

CYP2C19 is an enzyme of the Cytochrome P450 family of enzymes. The hepatic CYP2C19 enzyme metabolizes various drugs such as antidepressants, benzodiazepines, mephenytoin, some proton pump inhibitors, and clopidogrel into an active drug.

Genetic variants

The CYP2C19 gene is highly polymorphic with over 25 known variant alleles.

  • The CYP2C19*1 allele is the wild type that confers full enzymatic activity.
  • *2 allele result in the complete loss of enzymatic activity. This is the most common CYP2C19 loss of function alleles. Carriers of these allele form lesser amounts of the active metabolites and display a lesser extent of platelet inhibition.
  • Other variants have been identified as *3-*8 alleles that are also associated with reduced enzymatic activity.
  • CYP2C19*17 allele is seen to enhance gene transcription and is in turn associated with increased enzymatic activity.

Drug-Gene Relationship:

The CYP2C19 genotype and how it affects Clopidogrel metabolism

Extensive metabolizers

The presence of homozygous wild type allele *1/*1 is associated with functional enzyme activity. The carriers of this allele on administration of clopidogrel will form the active drug at normal rates and display reduced platelet aggregation.

Intermediate metabolizers

In heterozygous carriers of one functional (*1) and one non-functional (*2-*8) allele or one non-functional (*2-*8) allele and one increased activity (*17) allele, reduced platelet inhibition is observed.

Poor metabolizers

Homozygous or compound heterozygous loss of function allele carriers (*2/*2, *2/*3, *3/*3) show a significantly lower ability to inhibit platelet aggregation. This severely increases their risk of adverse cardiovascular complications.

Ultrarapid metabolizers

These individuals display enhanced platelet inhibition in response to clopidogrel therapy. They may even face the risk of increased bleeding and subsequent complications.

Table 1 depicts the allele frequency in certain populations, the effect of its presence on enzymatic activity and platelet aggregation.

 

Genetic Variant

Prevalence

Enzymatic Activity Level

Degree of Clopidogrel-induced Platelet Aggregation

*135- 50% of patientsNormalNormal
*2~15% in Caucasian and African Populations

29-35% in Asians

NoneReduced
*32-9% in Asians NoneReduced
*4-*8< 1% NoneReduced
*17~3-21% of populationIncreasedIncreased

Therapuetic Recommendations

Depending on the alleles present, the phenotypes observed have been classified into four groups. Table 2 shows how the pharmacological implications of having a particular genotype and the therapeutic recommendations for the same.

 

CYP2C19 Phenotype

Genotypes

Pharmacological Implications

Therapeutic Recommendations

Ultrarapid metabolizers*1/*17, *17/*17 Increased Platelet Inhibition.
Decreased Platelet Aggregation.
Standard Dosing
Extensive metabolizers*1/*1Normal Platelet Inhibition.
Normal Platelet Aggregation.
Standard Dosing
Intermediate metabolizers *1/*2,*1/*3,*2/*17 Reduced Platelet Inhibition.
Increased  Platelet Aggregation. Increased risk of CV events
Consider alternative antiplatelet agent such as prasugrel or ticagrelor
Poor metabolizers*2/*2, *2/*3, *3/*3 Significantly Reduced Platelet Inhibition.
Increased  Platelet Aggregation. Increased risk of CV events
Strongly recommended to consider alternative antiplatelet agent such as prasugrel or ticagrelor

Potential Benefits and Risks Involved

Results from a case controlled study have shown that carriers of CYP2C19*2 alleles are seen to experience early stent thrombosis. In cases like this where genotyping definitively predicts the outcome of therapy, the patients can be subjected to an alternative anti-platelet strategy. Moreover, testing laboratories should make an attempt to ensure that the results generated are error-free since even minor errors can adversely affect health outcomes in patients.

Caveats

As the results from the genotyping tests will determine the therapeutic course of action, early testing and expedited reporting will behoove the process.

 

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James Watson
Xcode is a pioneer in personal genomics, focussed on enabling personalized preventive healthcare. We are dedicated to empowering physicians, wellness professionals and customers with the most validated, accurate and actionable genomic information to positively impact and improve their client's health and quality of life.