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.
If not properly metabolized, clopidogrel may cause severe adverse cardiovascular effects due to non-optimal drug dose.
CYP2C19 is an important hepatic drug-metabolizing enzyme and is responsible for the metabolic activation of clopidogrel. Considering the pharmacogenetics of clopidogrel, genetic variants in CYP2C19 are known to impair the metabolism of this drug. Loss-of-function polymorphisms affect platelet inhibition by decreasing Clop-Am levels, resulting in an increased risk of recurrence of major adverse cardiovascular events.
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 adverse cardiovascular effects
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.
Cytochrome P450, Family 2, Subfamily C, Polypeptide 19, is a member of the cytochrome P450 superfamily with a significant action in clopidogrel metabolism
International Guidelines AND DRUG LABEL ANNOTATIONS
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 warns that patients who do not efficiently metabolize clopidogrel are at increased cardiovascular risk and therefore indicate that, when possible, the presence of non-functional CYP2C19 alleles should be tested. In these cases, it recommends that healthcare professionals consider the use of other antiplatelet drugs.
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 alternative antiplatelet therapy based on CYP2C19 genotype.
 Holmes et al., JAMA 306, 2704–2714 (2011)
 Mega et al., The New England Journal of Medicine 360, 354–362 (2009)
 Scott et al., Clinical Pharmacology and Therapeutics 94, 317–323 (2013)