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Plavix May Be Next on FDA’s List of Drugs To Relabel with Genetic Testing Data

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The US Food and Drug Administration is considering relabeling the widely prescribed anticoagulant Plavix with genetic information that could help identify best responders and help physicians make more informed prescribing decisions.
 
If the FDA goes through with the move, it would be the second anticoagulant after warfarin to have its label updated in such a way.
 
“We are actively looking at [Plavix] literature on both drug interactions, which creates functionally poor metabolizers, and genetic factors to see if there is enough evidence to warrant a label update,” Lawrence Lesko, director of FDA’s Office of Clinical Pharmacology, told Pharmacogenomics Reporter this week.
 
Plavix, commonly known as clopidegrel, is an anti-platelet agent used as a treatment for coronary artery disease, peripheral vascular disease, and cerebrovascular disease. Approved in the US over a decade ago, Plavix is prescribed to prevent vascular ischaemic events in patients with symptomatic atherosclerosis; acute coronary syndrome without ST-segment elevation, with aspirin; and ST elevation myocardial infarction.
 
Anticoagulants fall into three categories: inhibitors of clotting factor synthesis such as warfarin; thrombin inhibitors such as heparin and lepirudin; and anti-platelet drugs such as clopidegrel, ticlopedine, tirofiban, and eptifibatide.
 
Lesko, who made his comments following a talk at the Ohio State University Medical Center’s Personalized Health Care National Conference last week, brought up the example of Plavix in order to discuss how individual patient response cannot be predicted from studies designed to gauge population average response. 
 
Clinical trials with Plavix have shown that poor metabolizers of the drug could be at risk for “clopidegrel resistance.” According to Lesko, between 6 percent and 30 percent of patients given the drug experience less than 10 percent inhibition of platelet aggregation, which is defined in this case as treatment resistance.  
 

“[A] DNA test for 2C19 status would identify the subgroup of patients who would be resistant to clopidegrel.”

“Clopidegrel must be converted back to a metabolite by CYP2C19 to reduce aggregation,” Lesko explained. “It turns out the 31 percent of patients eligible for this drug have at least one *2 allele in this gene, which means they have reduced activity metabolically for clopidegrel.”
 
Studies have also shown that patients who carry the *2 allele also exhibit a three-fold increase in myocardial infarction or death one year after coronary stent placement.
 
This “brings the clinical significance of genomics to the forefront: Understanding that biology allows one to … reduce uncertainty of response by dealing with variability that has to do with 2C19,” Lesko said.
 
He clarified that while the enzyme 2C19 may be responsible for “clopidegrel resistance,” other receptor genetics, drug-drug interactions, as well as baseline platelet function may reduce the drug’s efficacy in some patients. 
 
“A resolution for a problem like this is challenging, no doubt, but a DNA test for 2C19 status would identify the subgroup of patients who would be resistant to clopidegrel,” Lesko added. This would be “actionable by giving a higher dose of the drug, or a different drug.”
 
Since Plavix was approved in 1997, the drug has been prescribed to more than 52 million patients worldwide. With $2.7 billion in worldwide sales for the six months ended June 30 — a 27-percent increase from the year-ago period — it is BMS’ best-selling product.
 
Other Relabeling Projects
 
A potential labeling update for Plavix would fall under an FDA effort started in 2002 to add genomic data to the prescribing information of older drugs. So far, the agency has relabeled the chemotherapies 6-mercaptopurine and irinotecan, warfarin, and the HIV drug abacavir with genetic information.
 
In 2006, the FDA’s Clinical Pharmacology Advisory Committee recommended updating tamoxifen’s label to include information about CYP2D6 testing, and the agency has said it is discussing this possibility [see PGx Reporter 11-15-2006]. 
 
Lesko suggested that the agency was considering once again updating the label for warfarin to include a stronger recommendation for genetic testing.
 
In August 2007, the FDA updated the label for warfarin to note that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. The agency did not require physicians to genetically test their patients, however, noting that additional outcomes studies would be necessary [see PGx Reporter 9-5-2007]. 
 
Since the labeling update, “more prospective and retrospective studies have been reported in the literature. We are actively looking into these data to determine if it would be possible and feasible to link label recommendations on dosing with genotypes of 2C9 and VKORC1,” Lesko told Pharmacogenomics Reporter in an e-mail this week.
 
“It is a complex area because both genetic factors and clinical factors determine dosing; an issue is how to simply convey recommendations in a package insert when so many factors are involved.”
 
In his presentation in Ohio, Lesko listed a number of drugs linked to genetics through various mechanisms, including the epilepsy and bipolar disorder drug carbamazepine, the opiate codeine, and the attention deficit hyperactivity disorder drug atomoxetine (Lilly’s Strattera).
 
“DNA-guided medicine requires us to change our mindset a bit, and focus on what’s really important in treating an individual patient,” he said. “Promoting the public health … means advancing the regulatory science and taking advantage of the scientific opportunities that present themselves.”

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