Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

Abstract

It is somewhat remarkable to note that not until recently, nearly 12 years and tens of millions of treated patients after its initial approval, has the metabolism of clopidogrel, an inactive prodrug, begun to be more fully understood. Although this lack of knowledge may not be unique among common cardiovascular drugs, there are 4 characteristics of clopidogrel therapy that make this gap in understanding disconcerting: The potential for life-threatening complications (bleeding or thrombosis) at both ends of its therapeutic spectrum; the fact that 1 dose is supposed to fit all; the lack of a measureable, proven end point (such as blood pressure for antihypertensive drugs) that allows for titration to a target response; and the nearly mandatory need by many patients for clopidogrel, with no acceptable alternative until recently. Article see p 512 Historically, understanding the metabolism of a drug has been critical in identifying those patients most likely to benefit from and, more important, potentially be harmed by that drug. This is especially true for drugs with relatively narrow therapeutic windows, such as phenytoin, warfarin, and others. Although it seems safe to assume, on the basis of our extensive clinical experience, that the therapeutic window of clopidogrel is unlikely to be narrow, this certainly does not represent the depth of knowledge we would hope for after so much clinical experience and research. What we do know is that P2Y12 inhibition with thienopyridines is beneficial in preventing arterial thrombotic events, presumably requiring the achievement of some minimal level of receptor inhibition that may or may not vary on the basis of the patient and clinical scenario. We also know that it is associated with a significant increase in serious bleeding events, with higher levels of inhibition associated with greater bleeding. In the present and future practice environment, with a growing …