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.