Pharmacodynamics. Clopidogrel bisulfate is an inhibitor of adenosine diphosphate-induced platelet aggregation. It directly inhibits adenosine diphosphate from binding to its receptor and the subsequent adenosine diphosphate-mediated activation of the glycoprotein GPIIb/IIIa complex. Clopidogrel acts by irreversibly modifying the platelet adenosine diphosphate receptor. Therefore, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Clopidogrel is a prodrug and requires metabolism via several CYP450 enzymes to exert its antiplatelet effects.
Inhibition of platelet aggregation occurs 2 hours after a single oral dose of clopidogrel. With repeated doses, it reaches a steady state within a few days, and the average inhibition level with a dose of 75 mg per day is between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued.
Approximately 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events, is still lacking. Clopidogrel resistance varies greatly depending on the method of measuring platelet aggregation and the definition of resistance, but rates of 8% to 18% were reported in 1 study (07). Clopidogrel resistance, which increases risk of major vascular events, is likely to develop due to a decreased bioavailability of the active metabolite, genetic variation, or concomitant drug treatment (27). A study on patients hospitalized following a noncardioembolic ischemic stroke or transient ischemic attack who responded poorly to clopidogrel showed discordant results on laboratory tests -- light transmission aggregometry and flow cytometric assays, using vasodilator-stimulated phosphoprotein and CD62P (28). Usefulness of transmission electron microscopy has been suggested when platelet function assay results disagree.
Pharmacokinetics. Important pharmacokinetic features are as follows:
Clopidogrel is rapidly absorbed after oral administration with peak plasma levels of the main circulating metabolite occurring approximately 1 hour after dosing.
After oral dosing, clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which represents approximately 85% of the circulating drug-related compounds in plasma and has no effect on platelet aggregation.
Approximately 50% of clopidogrel is excreted in the urine. The elimination half-life of the main circulating metabolite is 8 hours after single and repeated administration.
Clopidogrel resistance. This term is used for failure to achieve a drug response and may be due to a higher activation of platelets during clopidogrel therapy. Several contributing factors to clopidogrel resistance have been identified including genetic polymorphisms, concomitant use of other drugs, and vascular risk factors. Platelet function testing is recommended for patients with clopidogrel resistance, in whom an improvement in the efficacy of antiplatelet therapy is essential (29).
Pharmacogenetics/pharmacogenomics. P-glycoprotein encoded by ABCB1, a transmembrane calcium-dependent efflux pump for clopidogrel, is implicated in clopidogrel resistance. One study found that determination of ABCB1 genotype in addition to CYP2C19 enables better prediction of clopidogrel nonresponsiveness (19). Hypomethylation of ABCB1 promoter is associated with a decreased response to clopidogrel in Chinese patients with ischemic stroke via increased ABCB1 mRNA expression (31). The FDA has changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and clinical response. A systematic review and meta-analysis of published studies show that among patients with ischemic stroke or transient ischemic attacks treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers (21). There is still some controversy about the usefulness of CYP2C19 genotype testing in clinical use of clopidogrel. An ongoing meta-analysis of studies on the association of CYP2C19 genotype and clinical efficacy for stroke or transient ischemic attacks is expected to provide vigorous evidence on this issue to guide clinical decision-making as well as future research (32).
Genetic profiling is not recommended for routine use at present because CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response, and it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient (33). A polymorphism in the gene encoding PON1, a rate-limiting enzyme for clopidogrel bioactivation, also affects the response to clopidogrel (20). Because factors other than CYP2C19 genetic polymorphisms may contribute to the variability in antiplatelet effect seen with clopidogrel, adjustment of dosage is difficult. Ongoing trials dealing with adjusting antiplatelet therapy based on genetic testing will hopefully provide more useful information on how to integrate pharmacogenomics in the care of patients with atherothrombotic disease (08).
