Clopidogrel Pharmacogenomics and Risk of Inadequate Platelet Inhibition: US FDA Recommendations

Abstract

Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.

Prodrugs—from Serendipity to Rational Design

“…Therefore, the poor metabolizers are at significantly higher risk of suffering adverse cardiovascular events, such as myocardial infraction, stent thrombosis, and death. Many studies have demonstrated a consistent association between CYP2C19 genotype, clopidogrel pharmacokinetics, and clopidogrel pharmacodynamics in multiple populations, suggesting that the CYP2C19 genotype may be an important predictor of clinical response to clopidogrel (Ellis et al, 2009).…”

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…SNP variants of this enzyme interfere with the clinical activity of this drug, to the point where the FDA were induced to request a modification in the prescribing information of the drug. 9 More than 70 alleles of CYP2D6 and about 20 alleles of CYP2C19 have been identified with large interindividual and interethnic differences. The resulting CYP2D6 phenotypes can be classified into poor metabolizers (PMs), with two nonfunctional genes; intermediate metabolizers (IMs), including one nonfunctional and one reduced activity, or two alleles with reduced activity; extensive metabolizers (EMs), with at least one normal allele and ultrarapid metabolizers (UMs) due to the presence of more than two functional alleles (http:// www.cypalleles.ki.se).…”

Racial Differences in Resistance to P2Y12Receptor Antagonists in Type 2 Diabetic Subjects

“…Pharmacokinetic studies focus on metabolism of the prodrug clopidogrel as a mechanism of resistance (Gladding et al, 2008;Ellis et al, 2009); however, these studies did not account for altered platelet P2Y 12 receptor number or function (pharmacodynamic effects), increased circulating ADP, and upregulation of components of the P2Y 12 -receptor signaling cascade. As we observed a similar resistance to P2Y 12 antagonism utilizing a direct P2Y 12 antagonist in ex vivo platelets, we hypothesize that resistance to clopidogrel in T2DM patients (Matetzky et al, 2004;Angiolillo et al, 2005;Cuisset et al, 2006) is attributable at least in part to pharmacodynamic complications at the level of the receptor or its downstream signaling pathways.…”

“…Dual antiplatelet therapy consisting of aspirin and clopidogrel (the most commonly used P2Y 12 receptor antagonist) has become the standard of care in at-risk populations, including T2DM patients, for the treatment of acute coronary syndrome and following coronary stent implantation. Clopidogrel is a prodrug, and evidence suggests that loss of function in cytochrome P450 results in inadequate transformation to the active metabolite and resultant high residual platelet reactivity (Gladding et al, 2008;Ellis et al, 2009). But cytochrome P450 loss-of-function polymorphisms can only account for a portion of clopidogrel resistance (Shuldiner et al, 2009;Hochholzer et al, 2010).…”