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Introduction: Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics., Areas Covered: Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug-drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug-drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants., Expert Opinion: Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject.