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Clopidogrel Pharmacogenomics
Posted Jan 13, 2009
at 07:55 PM, EDT
by Eric Topol
3 new studies, 2 in the New England J of Medicine and one in Lancet on Dec 22 and 23 2008 have shed considerable light of the risk of a common variant of a cytochrome intimately involved withe metabolism of clopidogrel to its active metabolite----what are the implications???
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Eric J Topol MD
Director, Scripps Translational Science Institute The Gary and Mary West Chair of Innovative Medicine Chief Academic Officer, Scripps Health La Jolla, CA |
Comments
I'm a 61 y/o retired physician (radiologist) who had CABG x4 about 11 years ago. I have done well (no MI or stroke). I was found to have PlA2 variant so I have been taking clopidigrel. Is there any association of that finding with CYP 2C19? Does ASA help balance the CYP 2C19 allele variant effect? (I take 81mg ASA daily to blunt flushing from Niaspan).
Also, if one is taking clopidogrel and experienceing the usual easy bruising and prolonged bleeding, does that exclude the cytochrome variant issue?
I think this is a very important topic from a patient's perspective. It seems that ever since clopidogrel arrived on the scene complicated issues have arisen.
In addition to genetic variation, there are several other factors that can affect clopidogrel's pharmacokinetics and pharmacodynamics (i.e., inhibition of the platelet P2Y12 receptor), including: 1) physical variables (such as weight, BMI), 2) drug-drug interactions, 3) disease associated variables (e.g., acute coronary syndrome), and 4) patient compliance. There are now several publications, the most recent one in Circulation (Dec 31, 2008 online) that demonstrate that suboptimal inhibition of platelet function can result in serious consequences; including stent thrombosis and death in patients who have received drug eluting stents and are taking daily aspirin and 75 mg of Plavix.
By assessing the functional response of clopidogrel (ultilizing a measurement of platelet aggregation), one would obtain an integrated effect of all the factors cited above, as well as any other currently unrecognized variable that could potenitally impact platelet inhibition.
While measurement of platelet function has traditionally been both technically difficult and time consuming to perform, there is now at least one FDA-cleared assay that has been validated against standard aggregometry as well as correlated with clinical outcome, that is rapid, accurate, and easy to perform at the bedside and measures the effect of clopidogrel on platelet function.
If indeed platelet inhibition is impaired, further testing (including genetic testing), could be done to determine the specific cause and treat the patient appropriately.
Another corollary from the clopidrogel studies is that pro-drugs (ie, drugs that dependent on biotransformation to become active) are in general undesirable. With pro-drugs, you're adding another layer of uncertainty in the relation between administered dose and final pharmacodynamic effect.
Very interesting, with huge implications for business as well as the emerging practice of pharmacogenomics-based decisionmaking in prevention and treatment decisions. - Couple questions: when is FDA expected to make decisions about labeling of Plavix to recommend or require CYP2C19 genotyping, with or without any other tests for aggregation (roughly - 3 months? 6 months? more? any guess would be interesting)?
If doctors were to start ordering the genotyping to be done, who would be the likely first movers to offer genotyping and other assay services? Are there clear front-runners that are obvious providers of such tests at present, or not? Would pharma companies provide genotyping services if required, or would it be left to Dx companies?
How will information likely be disseminated to docs pre-FDA label decisions? It seems that Prasugrel's label restrictions re excessive bleeding have wounded potential competition. Are similar studies being carried out for Prasugrel's potential pharmacogenomic effects in varied genetic backgrounds?
I am amazed that I have completely missed this news, and that there are not more responses to this post/video. Thank you for putting it out there - this is one of the most interesting news I have heard in a while (of course, I am not a cardiologist but more of a recovering VC and entrepreneur with a soft spot for pharmacogenomics and population genomics technologies).