Luigi Silvestro

Clopidogrel presents a complex metabolism; in last years’, special attention was dedicated to identify genotypes resistant to treatment and FDA introduced a boxed warning in product leaflet for specific patient groups. Meanwhile it was observed that statins (some), proton pump inhibitors and other drugs interfere significantly with clopidogrel metabolism. In this study, patients (n=213) hospitalized for major cardiovascular problems (stable angina, ST elevation myocardial infarction, non-ST elevation myocardial infarctions) were given clopidogrel and followed clinically ≥2 years; patients received also other drugs (i.e. statins, antidiabetic, aspirin etc.) for concomitant pathologies and/or other invasive therapy (i.e. stenting) according to their lesion severity. All subjects were CYP2C19 genotyped (considered critical by FDA) and plasmatic levels of clopidogrel and 3 relevant metabolites (including the active-one) were determined at one time point to assess PK characteristics. Three groups of data were then obtained (clinical, genotype and PK) and correlations between them were statistically analyzed. Extremely interesting results have been obtained: 1) Genotype data actually poorly correlated with clinical data; 2) Clopidogrel PK seems unrelated to genotype while metabolites PK, especially of inactive-ones, correlate very well; 3) Concomitant therapies with several drugs have a highly relevant influence on clopidogrel metabolites PK (less with clopidogrel parent); 4) PK data of metabolites correlated very well with subjects survival. These data show the importance to carefully choose concomitant therapies when using clopidogrel, while genotype seems not to be as relevant as thought; the evaluation of clopidogrel metabolites PK is highly promising in clopidogrel therapy optimization.