Clopidogrel is a drug used worldwide as an antiplatelet agent in the treatment and prevention of atherothrombotic events. Being a prodrug, clopidogrel needs hepatic bioactivation into an active form (Clo-AM) in order to inhibit platelet aggregation. CYP2C19 is an important hepatic drug-metabolizing enzyme and is responsible for the metabolic activation of clopidogrel.
If not properly metabolized, clopidogrel may cause severe adverse cardiovascular effects due to non-optimal drug dose. The clinical importance of CYP2C19 genotype affecting clopidogrel pharmacokinetics and pharmacodynamics has been extensively studied in the recent years.
CYP2C19 genetic variants have been shown to impair the metabolism of clopidogrel. Loss-of-function polymorphisms affect platelet inhibition by decreasing Clop-Am levels, resulting in an increased risk of recurrence of major adverse cardiovascular events. Conversely, gain-of-function polymorphisms are associated with increased risk of bleeding.
Benefits of genetic testing
By evaluating CYP2C19 genetic variants it is possible to:
- evaluate the patient response to clopidogrel
- prescribe an adequate dose
- define alternative antiplatelet therapy.
- avoid the adverse side-effects of non-optimal warfarin dosage
The genetic test evaluates 3 genetic variants in the CYP2C19 gene (9 haplotypes ) that are associated with clopidogrel’s pharmacokinetics. The polymorphisms can either increase (gain-of-function alleles) or decrease (loss-of-function alleles) the catalytic activity of CYP2C19 enzyme resulting in phenotypes that affect clopidogrel metabolism and consequent platelet inhibition.
- CYP2C19 – Cytochrome P450, Family 2, Subfamily C, Polypeptide 19, is a member of the cytochrome P450 superfamily with a significant action in clopidogrel metabolism
International Medical Guidelines
Genetic testing is recommended by several renowned international organizations, such as the Food and Drug Administration (FDA) and the Clinical Pharmacogenetics Implementation Consortium (CPIC)
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 the 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
The Clinical Pharmacogenetics Implementation Consortium (CPIC) that develops peer-reviewed gene-drug guidelines based on new developments in the field, has established several recommendations on clopidogrel dosage based on CYP2C19 genotype.