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Massive British Study Seeks to Understand Pharmacogenomics of Warfarin Response

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British researchers will soon begin a large prospective study that looks at the pharmacogenomics of the widely prescribed anticoagulant warfarin, according to a project investigator.

The study, which will follow 2,400 individuals, looks at genetic and environmental contributors to drug response. It may also be able to describe a role for pharmacogenomics in treatments involving ubiquitous, cheap generic drugs such as warfarin.

The ultimate product of the research will be an algorithm that uses environmental and genetic data to help predict appropriate individual dosages, the scientist said.

“Clearly, there are many other studies going on with other drugs, but given that warfarin is so widely used and has a very low therapeutic index, it is an ideal drug to study with regard to pharmacogenetics,” said Munir Pirmohamed, a researcher with the University of Liverpool and lead author of the study.

Warfarin is commonly prescribed to patients with an irregular heartbeat, or who have had a heart attack or heart valve replacement surgery. The drug is used by as many as 1 percent of all Britons, or about 600,000 people, and approximately the same percentage of Americans, according to Pirmohamed.

“There is a great deal of variability in how patients react to warfarin in terms of dose requirements,” said Pirmohamed. “Also, there’s a risk of over-anticoagulation in certain patients, plus resistance in some patients that require higher doses.

“There is some evidence that genetic factors may be important, but there has not been a prospective study that has looked at genetic and environmental factors,” he added.

The study will follow 2,000 patients for six months, starting from the time they begin taking warfarin. A separate research team will study 400 more individuals, who serve as a validation cohort. Pirmohamed and his colleagues will collect patients’ phenotypic data, including information about anticoagulation, biochemistry, and pharmacological factors — especially warfarin levels.

To produce a dosage algorithm, the researchers will relate that information to genetic data on 25 candidate genes, narrowing down the list to those most important to warfarin response.

No large pharmacogenomic study to date has taken into account the variance of several environmental factors and genetic factors to determine their combined impact on drug response, and the interactions among them, said Pirmohamed.

Research into warfarin and other anticoagulant drug responses follows a vein similar to that of statins. Both classes of drugs are cheap and widely used, while having clear genetic components to their side effects. For example, Genaissance, the New Haven, Conn.-based pharmacogenomics company, participated in a clinical trial that studied the influence of 1,500 haplotypes among 100 genes on patients’ response to certain statins [see 1/31/03 PGx Reporter].

The genetics of warfarin drug response are well understood, and side effects to the drug are relatively rare, said Richard Judson, vice president and chief scientific officer of Genaissance. “It’s the perfect kind of study for genetic analysis. I think it has a good chance of finding something important and interesting for people taking this drug.”

Warfarin is metabolized by members of the cytochrome P450 family. Cytochrome alleles CYP2C9*2 and CYP2C9*3, for example, are closely associated with impared s-warfarin metabolism. Patients carrying these genetic variants can develop side effects due to high bloodstream drug levels.

“I think the field of pharmacogenomics needs examples of success,” said Judson. For example, the understanding of warfarin will have a huge clinical impact in the development of new cancer drugs, and the use of existing drugs, due to the huge number of patients currently taking warfarin, he said. “I think the field is advanced enough that this is a great example of how what we’ve learned over the last 5-10 years is going to be used.”

If pharmacogenomics is to expand into areas dominated by cheap drugs taken by large patient populations, it will be because studies like Pirmohamed’s find good candidates for early commercialization, said Judson. “The field is looking for commercial products to show that there is money to be made and patients to be helped.”

Pirmohamed’s study is currently undergoing ethical review, and it should be starting within the next couple of weeks, he said. Working with his University of Liverpool group are researchers at the Royal Liverpool Hospital, the University of Birmingham, the University of Newcastle, the University of York, and the Sanger Institute.

Funded by the United Kingdom’s Department of Health, the £850,000 ($1.5 million) study is part of a £4 million effort to study pharmacogenomics, which is itself a product of a £50 million public health strategy announced in a 2003 Genetics White Paper in the UK.

Other research projects supported by the UK Department of Health’s pharmacogenomics funding include: a screen for individuals at risk for malignant hyperthermia, which is a reaction to common anesthetics; an exploration of the genetics of patients who suffer adverse reactions from the anti-inflammatory drug azathioprine; research on the genetic bases of liver damage caused by penicillin and anti-tuberculosis medicines; a project to predict responses to the anti-epilepsy drug clobazam; and a research project to identify the genetic predictors of heart damage caused by anthracyclines, which are effective cancer drugs.

The UK Department of Health and the FDA are “picking off all of the drug side effects that seem to have a genetic component, going after them one at a time, and finding a marker and doing something with it,” said Judson. “So I think that’s a practical program for the funding agencies to encourage.”

— CW

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