Pharmacogenomic Advances Result in Label Changes Decades after Approval

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BETHESDA, MD—Even drugs that have been on the market for years, sometimes decades, are not immune from reexamination and relabeling brought about by new scientific discoveries. In the field of pharmacogenomics especially, new opportunities are presenting themselves to use new science to improve drug safety and dosing protocols.

“There are many factors that affect drug exposure and response,” said Shiew-Mei Huang, PhD, deputy director of FDA’s Office of Pharmacology, at a talk on the campuses of NIH. “The ultimate goal is to provide the most precise labeling for patients.”

For example, Crestor®—a statin marketed by AstraZeneca—recommends an initial dose of 10 to 20 mgs and a maximum daily dose of five to 40 mgs. However, due to data from studies looking at factors that could affect specific patient response, physicians know that patients with severe renal impairment are especially sensitive to the drug, and need only a five mg initial dose. Also, differences have been shown between Asian and Caucasian response to Crestor, resulting in a lower recommended daily dose for Asians, who are more sensitive to the drug.

“We have to consider pharmacogenomics in advising what doses to administer,” Huang said.

Safety-related labeling changes can occur many years after initial drug approval. Warfarin—an anticoagulant marketed under a number of brand names—was approved in the early 1950s. However, the drug has historically been underutilized due to physician and patient fear of excess bleeding. According to FDA, the drug is prescribed to only two-thirds of appropriate candidates.

Part of that fear is due to the difficulty in managing the drug. There are wide variations in drug reaction, only 15% of which can be explained by clinical factors. However, recent revelations in how genetics play a part in warfarin sensitivity help
explain more than 50% of the variation in drug reaction.

Genomic studies looking at the VKORC1 and CYP2C19 genes show that variations in those genes can lead to either sensitivity to the drug or resistance. Polymorphisms in the VKORC1 gene result in African Americans generally being more resistant to the drug, and requiring a higher dose than the normal two to five mgs. A different polymorphism of the same gene results in Asians generally being more sensitive to the drug and needing a lower dose.

“We first introduced genetics [to the labeling] in 2007. There were many criticisms because there was no actionable recommendation in the labeling,” Huang said. “This year, we came up with a table in the labeling explaining what variations of the genes mean when it comes to dosing.”

Similar pharmacogenomic interactions occur with clopidogrel, an antiplatelet marketed under the name Plavix® by Sanofi Aventis. First approved 14 years ago, clopidogrel was recently found to react differently in patients with a particular variation of CYP2C19. Those with the variation poorly metabolize the drug, and the result is a higher rate of death from cardiovascular causes in that genotype group. In January 2009, FDA provided early communication about the discovery; added labeling changes in May 2009; and added a black box warning regarding “diminished effectiveness in poor metabolizers” in March 2010.

“We are always thinking about clinical utility,” Huang said. “That is helping us get to the clinically meaningful recommendations.”

Those recommendations have resulted in the fielding of tests designed to determine a patient’s CYP2C19 status prior to antiplatelet therapy.

“We are seeing more applications of physiological-based modeling to evaluate patients when they have multiple factors—genetics, drug interaction, renal impairment,” Huang said. “Individual variations in drug response may be attributed to intrinsic and extrinsic factors, and genetics is one of them. It is important to assess various subgroups during drug development.”

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