By DFK | March 12, 2013 at 10:41 AM EDT |
12 comments
Yesterday in The Wall Street Journal, an article appeared entitled 'Plavix Disclosures are Probed'. Here are two portions of the Monday March 11, 2013 article by Peter Loftus:
'In 2010, the U.S. Food and Drug Administration added a boxed warning to the prescribing label for Plavix about the potential for reduced effectiveness in a subgroup of patients who metabolize the drug poorly.'
'At least two state attorneys general...have alleged that the [manufacturers] should have known since 2003 that Plavix has reduced effectiveness in patients who metabolize it poorly. The suits allege the companies failed to disclose that information in a timely manner because they wanted to preserve Plavix sales.'
This article brings up the whole issue of metabolizer status or metabolizer phenotype. The phenotype is the 'expression of an individual's physical trait or physiologic function due to genetic and environmental and other factors.' Here, we will focus on the genetic influence.
Plavix (clopidogrel) is a prodrug, meaning it must be converted to an active form to work. The enzyme responsible for this conversion is CYP2C19 and the following information is related to this enzyme. Individuals who are 'normal' metabolizers (with a normal gene from each parent) are also called extensive metabolizers or EM. People who get one common, normal gene from a parent and one loss-of-function gene from the other parent are heterozygotic (a different form from each parent) from the genetic sense and are considered 'intermediate (IM) metabolizers'. Individuals with two loss-of-function forms are considered 'poor metabolizers (PM), being homozygotic (same form from each parent) in the genetic sense. It is this population that is referred to in the Wall Street Journal article. Some individuals have increased metabolism and are considered 'ultrarapid' metabolizers.
The following are some thoughts about clopidogrel and the metabolizing phenotype. Also, the "star" nomenclature is provided as example genetic 'constitution' called the genotype:
EM (*1/*1 genotype) - normal dose of clopidogrel should provide therapeutic benefit
IM (*1/*2 genotype; there are others that cause a person to be an IM) - normal dose of clopidogrel may not provide therapeutic benefit to patients who have undergone stent (small tube) placement in the coronary arteries of the heart. While a larger dose would theoretically be needed so more drug could be converted to the active form, these individuals should be switched to a different therapy.
PM (*2/*2 genotype; there are others that cause a person to be a PM) - a different drug should be used for these individuals.
UM (*17/*17 genotype) - normal dose of clopidogrel should provide therapeutic benefit. There may be an increased risk of bleeding.
So, what does JES's data show? The 23andMe report states ‘Clopidogrel (Plavix®) Efficacy’. OK, to me this implies that JES is an EM, with a *1/*1 genotype having received the ‘normal’ CYP2C19 gene from each parent, i.e. no SNPs. Digging a bit deeper, here is the information I found:
JES in fact has a SNP, rs12248560. The rs number is a unique and consistent identifier of a given SNP as found in the National Center for Biotechnology Information (NCBI) database. In this case, the rs12248560 refers to T replacing C at a specific location on the CYP2C19 gene. Not only did JES have a T at that position from one parent, he had a T at that position on the gene from his other parent...making JES a *17/*17 ultrarapid metabolizer!
Now remember, relative to clopidogrel, a UM will readily convert the parent (inactive) compound to the active form. This active form is the therapeutic beneficial form.
Here is a challenge. Consider drugs that are active as the parent compound (i.e., not a prodrug). Tell us what may be the expectation for effectiveness of drug therapy with other drugs metabolized by CYP2C19 in JES.
The first idea I could come up with is that a drug that is active as the parent compound, if made contact with the enzyme would be changed, and render that drug ineffective for its treatment. That means JES would need more of that drug than normal due to his UM for Plavix.
If a drug is active as the parent compound, it could act as an inhibitor of CYP2C9. With the various usages of drugs in drug therapy, a prodrug might not work for the patient because the CYP2C9 is inhibited. Nifedipine is an inhibitor of the enzyme and it is found in antihypertensive medications, which is related to the reason of the usage of the blood clot preventative.
I believe that the effect varies depending upon genetics, and in JES's case could cause the drug to become inefficient. Therefore, a newer measure must be needed to account for the possibility of a parent compound becoming inactive. I would first attempt to place JES on a higher dosage, but if that does not work he could need an alternative medication that takes the inhibitor of CYP2C9 into account. However, special attention must be taken because a *17/*17 could bring an increase risk of bleeding.
In my opinion, the drug would be ineffective for JES. An enzyme changes its substrate. In the case for a prodrug, the product produced would be the active form of the drug. But for an active drug, the enzyme would change the substrate into what would most likely be inactive. So in JES's case, I would guess that since he is an UM he would need a different drug because the medicine he were to take would be changed to an ineffective form.
I like what I am hearing so far. I see a couple of references to CYP2C9. Here, were are talking about CYP2C19. Of course the same principles hold. Let's provide some specific drugs as examples. I want to see what we can come up with.
So this really made me think.I think that Aggrenox is an alternative to plavix that still acts as a blood thinner. If JES took other drugs that were metabolized by CYP2C19, then he would be a UM with them as well.
CYP2C19 ultrarapid metabolizers have a higher probability of failing plavix and other drugs metabolized by this enzyme( such as prilosec or PPIs)due to bleeding, and alternate agents are preferred. I feel that there is still insufficient data in the literature to calculate a starting dose for a patient with CYP2C19 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended.
If some other drugs that are active as the parent compound (such as moclobemide, fluvoxamine or chloramphenicol) are taken along with plavix, then the CYP2C19 enzyme will be inhibited and it will not be able to metabolize and activate drugs such as plavix, and potentially induce atherosclerosis and possibly a heart attack in such patients.
According to this study,
http://www.cardiosource.org/~/media/Files/Science%20and%20Quality/Clinical%20Trials/PLATOgenetics.ashx
the drug ticagrelor, which was fairly recently approved by the FDA, works better than clopidogrel irrespective of CYP2C19 polymorphisms. I think this would be a much safer route for JES.
There is a greater chance of bleeding with clopidogrel in ultrarapid metabolizers, and other (non prodrugs) would be less likely to work. The use of prasugrel and ticagralor is rationale, however, new information will be forth coming on these drugs. There is certainly an economic benefit to using clopidogrel where it can be used.
A UM would require more of an active drug because the drug would be removed from his systems faster. I think it's fascinating that JES has such am uncommon SNP. Other drugs that are effected by the CYP2C19 gene include: Carisoprodol, Ticagrelor and Omeprazole. JES might need an increase in any of these drugs.
UM have a larger quantity of the enzymes that react with the prodrug. This may cause the active drug to have a greater affect. However, when parent drugs are introduced to an UM, a higher dose may be necessary to have the desired affect upon the individual. So, parent drugs that are introduced to JES and metabolized by CYP2C19 may require higher doses to be effective.
If he were to have a \"normal\" dose of the drug it probably wouldn't have much affect on JES. He would need to have a higher dose of these parent drugs to have the desired response.