It is now well documented that platelets play an important role in the pathogenesis of acute coronary syndromes. This phenomenon has significantly strengthened the position of antiplatelet drugs in treatment, and prevention of these syndromes. In terms of administration, antiplatelet drugs are divided into two categories, the oral and intravenous medications. Of these, oral medications are the choice for long-term or prophylactic treatment of patients with acute coronary syndrome. Among them, is clopidogrel, which together with aspirin is now the cornerstone of antiplatelet therapy. Indeed, clopidogrel is a widely used antiplatelet drug. It is second in sales worldwide after atorvastatin and has been prescribed to more than 100 million patients worldwide. Clopidogrel can be used as monotherapy or in combination with aspirin. The efficacy in reducing ischemic events in patients with ACS has been shown in more than 15 major clinical studies involving more than 200,000 patients. These studies also proved the safety of clopidogrel to the bleeding complications (only 1-2% per year).Clopidogrel is a second generation thienopyridine that inhibits the binding of ADP to purinergic receptors of platelet membrane. The ADP activates platelets through different receptors coupled to G-proteins. The main receptor for platelet activation by ADP is P2Y12, associated with the adenyl cyclase and cause deactivation of the resulting reduction in the levels of c-AMP. The identification of this receptor led to the complete elucidation of the mechanism of action of clopidogrel, which proved to be an irreversible antagonist P2Y12.
Clopidogrel is a prodrug that, once granted, is absorbed in the intestine by a process in which an important role is played by the protein carrier ABCB1/MDR1. Then clopidogrel is converted in the liver to the pharmacologically active metabolite by the action of cytochrome P450 (CYP450) and mainly isoform CYP2C19 and isoforms CYP3A4, CYP3A5, CYP1A2, CYP2B6 and CYP2C9. It should be noted that 85% of clopidogrel absorbed, hydrolyzed by esterases in the intestinal mucosa and blood to form biologically inactive products while only 15% of the administered drug is converted to its active metabolite, which is a potent, irreversible, selective inhibitor of receptor P2Y12 ADP resulting in the inhibition of the activation of receptor GPIIb / IIIa and thereby preventing platelet aggregation.
Currently, clopidogrel generic forms are available in the market. Indeed, in 2010 and after 10 years of circulation of the original formulation (clopidogrel bisulfate) under the trade names Plavix or Iscover, released new generic formulations of clopidogrel (generic) due to expiration of the period of exclusive marketing using the original formulation. Main difference of generic forms of clopidogrel to the original formulation (clopidogrel bisulfate) is pharmacochemical recommendation salt of clopidogrel, which in the case of generic formulations is benzenesulfonic (besylate) or hydrochloride salt. Generic formulations of clopidogrel have received marketing approval from the health authorities of the European Union. Bioequivalence comparative studies of clopidogrel generic formulations in healthy volunteers for generic clopidogrel bisulfate, clopidogrel besylate and clopidogrel hydrochloride have proven same pharmacodynamic and pharmacokinetic profile. Considering the wide variability of platelet response to clopidogrel treatment and the high incidence of atherothrombotic events in clopidogrel hyporesponsive patients, studies comparing the pharmacodynamic properties of various generic clopidogrel formulations with those of original clopidogrel bisulfate in CAD patients are essential.
Therefore, given the numerous generic clopidogrel salts that are commercially available today, it is of importance to note that any clinical data or research results arising from the use of these formulations in patients with cardiovascular disease should be related to the specific product used and not generally to the generic clopidogrel.
Our group has performed two prospective pharmacodynamic studies comparing the antiplatelet effectiveness of clopidogrel besylate with that of clopidogrel bisulfate in patients with a history of an ACS, and in ACS patients undergoing PCI. In both studies we showed pharmacodynamic bioequivalence in all platelet function tests performed.
There is a strong need of conducting further clinical studies with adequate number of patients with each clopidogrel generic formulation commercially available in order to confirm its therapeutic equivalence with the innovator product.
