Impact of Genetic Polymorphisms and Drug – Drug Interactions on Clopidogrel and Prasugrel Response Variability

V.      Ancrenaz; Y.      Daali; P.      Fontana; M.      Besson; C.      Samer; P.      Dayer; J.      Desmeules

Abstract

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxoclopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug – drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug – drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug – drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug – drug interaction affecting clopidogrel and prasugrel antiplatelet activity.

Keywords: Clopidogrel, cytochrome P450, interaction, pharmacokinetic, pharmacodynamic, pharmacogenetic, platelet, prasugrel, atherosclerotic plaque, acute coronary syndrome, percutaneous coronary intervention, thienopyridines, P2Y12-adenosine diphosphate (ADP) receptor, CYP2C192, CAPRIE, transient ischemic attack, CHARISMA, NCT00642174 (OPTIMUS-3), CYP3A4, CYP2C19, CYP1A2, ABCB1, Carboxylesterases Polymorphism, human carboxylesterases, cytochromes P450, carboxylesterases, HCE1, HCE2, MACE, rs12248560, CYP3A, CYP2B6, 2C9, 2C19, omeprazole, esomeprazole, lanzopra-zole, rabeprazole, pantoprazole, COGENT, Thrancatheter Cardiovascular Therapeutics (TCT), VASP assay, stent thrombosis, revascularization, Ketoconazole,, prasugrel+rifampin group, Antiretrovirals, 2B6 in-hibitors