February 8, 2023

– July, 2010. Robert Cole M.D., Chief Medical Officer of AutoGenomics

My name is rom vera van i’m a senior vice president at auto genomics i would like to take this opportunity to invite you to auto genomics to participate in a couple of presentations that we have arranged for you during the course of this show topics of interest of clinical interest kind of academic interest the very first presentation today is going to focus on

Clopidogrel and to see 19 and as a chair of this session we have dr. robert cole who’s the chief medical officer of auto genomics and on our panel we do have dr. alan boo who is from the university of california san francisco and dr. glenn mcmillan from a rup salt lake city we have an exciting presentation so at this stage i would like to invite dr. cole and hand us

Over so today we’re going to talk about the relevance of the black box warning to clopidogrel therapy and let’s begin first of all by just a minor introduction into pharmacogenomics pharmacogenetics we understand that pharmacogenetics or personalized medicine is in we are engaged in the process of doing genetic evaluations on patients to determine what the right

Drug will be with the right dose and what they’ll potentially with the right patient for that drug will be the choice of therapy can be predicted by specific genetic changes that can be tested clinically our clinical goals for pharmacogenomics are to avoid adverse drug reactions to maximize drug efficacy to select responsive patients and defined individualized

Drug dose now if we look at this this chart i’m sure many of you’ve seen as it turns out only about fifty to sixty percent of the patient population drugs are really designed for and members sub members of the population the drug may be toxic but beneficial for those patients there were the drug is toxic we may have to consider to reduce the drug a reduce the

Dosage or change the drug for some members of the population the drug may not be toxic but not beneficial at the standard dose and for those patients we have to consider increasing the dose to get the benefit that we’re looking for for other patients the drug may be toxic but not beneficial for those patients we would consider using a completely different drug and

Then we have the population which the drug was probably designed for over here in the other corner we’re going to be talking about some specific elements of the metabolism system that is involved in helping making those predictions the cytochrome p450 system is a large family otimo proteins there’s central importance in metabolizing a large number of endogenous

And exogenous molecules in the liver these substrates include drugs and toxic compounds sips are the major enzymes and rub involved in drug metabolism and we’re talking about clopidogrel later we’ll hey we’ll be talking also about not only metabolism but bioactivation the genes include encoding sip enzymes though are polymorphic we use the term polymorphic to

Represent the fed to indicate that there are individual differences in the way these enzymes function from one person to the next now the sip to see 19 enzyme is involved in metabolism of a variety of different drugs including allied depressant anticonvulsant proton pump inhibitors cytotoxic agents beta blockers anti estrogens and antimalarials we’re going to talk

Today though specifically about plavix now plavix is known at the generic name is clopidogrel bisulfite there are over 90 million patients worldwide on the drug now what are the indications for plavix acute coronary syndrome these are patients that are having chest pain many of these patients will require an interventional interventional evaluation in the form of

An angioplasty or stem a stent placement for these patients we are concerned about alterations in endothelial lining of the vessels to the heart and we’re concerned about the development of clot formation so giving plavix is an important drug to reduce clot formation and reduce platelet aggregation patients that i have i’ve had a recent myocardial infarction may

Also be placed on this to once again to reduce platelet aggregation recent strokes and patients that have had / established peripheral artery disease now the mechanism of action now plavix is a prodrug that irreversibly inhibits adp receptor p2y12 which is on the platelet cell membrane which is essential to platelet aggregation it’s important to recognize this is

An irreversible binding so once once this drug has bound to the receptor site on the platelet that platelet is essentially taken out of commission now the dosage varies for the most part we are maintenance dosage is 75 milligrams but we can bump that many patients up to 150 milligrams without significant side effects loading doses we want to get maximum effect for

Patients particularly you’ve had in a cardiac intervention loading dose can be either 300 milligrams or 600 milligrams their balls have certainly been studies where we looked at higher loading doses as well okay now clopidogrel once again is a prodrug that has to be converted to the active metabolite to see 19 is the key enzyme in this process gc 19 is a polymorphic

With multiple variants resulting individuals with the reduced ability to convert clopidogrel to the active form of the drug now there are several snips that are important the key principle reduced function polymorphism is start to there are additional reduced function polymorphisms that are 3 4 5 6 7 8 9 and 10 also important is an increased function polymorphism

This is star 17 for these patients they are actually going to bio activate more of the plavix than a standard patient so these patients are going to have a greater effect of plavix if they are exhibiting the star 17 polymorphism now is this a rare event actually it turns out it’s not a rare event if we look at these polymorphisms are quite common in the population

Thirty percent of caucasians have them forty percent of african-americans and fifty-five percent of asians now mega in in the new england journal of medicine in december of last year wrote a significant article about clinical outcomes of people that were manifesting these polymorphisms and there’s been a flood of literature looking at the genetic causes of this

Variability and how this individual variability can affect clinical outcome from that flood of literature important event occurred in march of 2010 which was the fda black box black box warning we’ll talk a little bit more about the this is generated controversy and concern anytime a warning like this goes on a drug that is being used to this degree and involved

In acute medical situations that involve life and death this will generate a great deal of concern on the parts of patients on a part of positions and certainly a patient’s have read this are going to be concerned about this as well it’s important to look about a look at what this black box says and what it doesn’t say the black black box does not say that all

Patients need to be tested it does explain that there are patients that can be poor metabolizers and that this is reflected in the to see 19 this is reflected in a to see 19 gene and the tc 19 status can impact the effect of the drug and there they talked about although higher dose regimen a loading dose of 600 milligrams followed by a hundred fifty milligrams

In poor metabolizers increases antiplatelet response an appropriate dose regimen for poor metabolizers has not been established in a clinical trial now any time you as a box like this is significant this has eight this has a huge effect on physicians in the way they practice there’s always the background of a medical legal issues practice as an obstetrician for

25 years i spent a lot of time thinking about medical legal issues i’m sure cardiologists consider this as well now eric topol has been an advocate of genetic testing for a long time he wrote a very compelling opinion piece in the journal of the american of the american college of cardiology he makes three major statements that i think are important he says

The evidence threshold supporting in duvall individualized political therapy has been clearly surpassed the also states we cannot afford to wait years for the results from trials which have yet to be initiated think this is an important point that he makes that the true multi-armed trials looking looking into this question have not yet been designed and are not

Presently underway so we have years to wait before we have the complete answers to the questions that are that are hanging over us and here’s his position is that we should implement all potential interventions to help prevent the catastrophic outcomes of stent thrombosis and death in the tens of thousands of patients currently at risk and we have a recent article

Clinical alert put together by the american college of cardiology foundation task force and the american heart association and this is this is their comment about the black box a it serves to make clinicians aware of the imperfect but significant knowledge that we have about genetic variation in response to clopidogrel and to emphasize that clinicians should use

This knowledge to make decisions about how to treat individual patients now i think it’s important to recognize what they’ve said they said if the knowledge is there for you you should use that knowledge to make a clinical decision about how you’re going to treat this how you’re going to treat the patient they fail to state whether you should go out and search out

That knowledge and that remains to be the controversy that will will be resolved you know hopefully in the near future and not the long term just to follow up the the clinical alert i think is a very balanced and appropriate exploration of these issues they talk about the evidence on variability of political response the current status of ship to see 19 genotyping

Assays they discuss alternative doses dosing regimens for clopidogrel they also talk about medication substitution and they also review ongoing trials but today to date the ongoing trial that we really need to design to answer these questions have yet to be instituted and we’ll have to wait to see what the answers will be so that i’m going to pass it over to dr.

Allen whew i have instituted on to see 19 graham at my hospital based on the information from the fda in the black box warning and

Transcribed from video
Relevance of Black Box Warning to Clopidogrel Therapy By AutoGenomics