AI
Saturday, August 18, 2007 10:03:15 AM
The FDA could require DNAPrint's test
(Something similar to Warfarin- see below!)
DNAPrint published in Pharmacogenetics and Genomics
http://www.jpharmacogenetics.com/pt/re/pharmgen/currenttoc.htm;jsessionid=GGMdwC31xTF4QW0HpvJ8nyySTl....
CYP2D6*4 polymorphism is associated with statin-induced muscle effects.
ORIGINAL ARTICLES
Pharmacogenetics & Genomics. 17(9):695-707, September 2007.
Frudakis, Tony N.; Thomas, Matthew J.; Ginjupalli, Siva N.; Handelin, Barbara; Gabriel, Richard; Gomez, Hector J.
Abstract:
Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena.
--------------like this below!!!
FDA Pushes Genetic Test Tied to Warfarin
[Doctors worry about malpractice liability if the test is not performed.]words from Dew Diligence.
http://online.wsj.com/article/SB118722561330199147.html
By ANNA WILDE MATHEWS
August 16, 2007
In May, Karen Schmale was rushed to Barnes-Jewish Hospital in St. Louis, gasping for air. Diagnosed with blood clots in her lungs, she was given a powerful blood thinner called warfarin.
The medicine probably helped save her life. Then it almost killed her. About a week later, Ms. Schmale, 49 years old, noticed blood in her urine and soon became so weak she could barely climb the stairs to her second-floor apartment. The warfarin was causing the bleeding, and she had to go back to the hospital for an emergency blood transfusion.
A genetic test revealed Ms. Schmale was unusually sensitive to the drug and needed a smaller dose. Before the test, "nobody knew I was going to react like that," says Ms. Schmale, a data-entry coordinator at a university in St. Louis.
The case shows the advances in personalized medicine, where treatment is tailored to an individual's genetic makeup. But, in a possible harbinger of battles to come, the warfarin tests have also led to a clash between the Food and Drug Administration and some doctors.
The FDA is set to announce today that warfarin's label will carry new information describing the role of genetics in dosing. The label will say that a lower initial warfarin dose "should be considered for patients with certain genetic variations."
Some specialists say testing hasn't been proved to reduce the risks of the drug. They fear patients who don't get the tests and run into trouble will sue doctors, citing the drug's label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don't. The insurers say they need more evidence about the benefits.
"It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label," said University of Washington professor Ann Wittkowsky in an interview before the FDA's decision. "It is fascinating science, but it is not yet ready for prime time."
Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has "substantial" evidence to support the new label and hopes it will improve safety by informing doctors.
Dr. Lesko is part of a larger initiative at the FDA to promote the use of genetic factors to predict how individuals will react to medicines. It's a shift for the agency, which traditionally has more of a reactive role as the regulator of the drug industry. "If the potential wasn't huge, we wouldn't be doing it," he says. "We felt we had to be more outspoken."
The agency has already included information about genetic testing on the labels of less-frequently used drugs for colon cancer and leukemia, among others. One drug, Genentech Inc.'s Herceptin for breast cancer, is designed especially for women whose tumor cells have a genetic abnormality.
But warfarin is the largest case study to date of what happens when the new science of genetics runs up against the everyday practice of medicine. Originally marketed as a rat poison, the drug was prescribed more than 30 million times last year in the U.S., according to IMS Health. It's available as an inexpensive generic pill.
Its main problem is the narrow window for safety. An excessive dose leads to bleeding. Warfarin is the second-most-likely drug, after insulin, to send Americans to the emergency room. By one estimate, it accounts for 43,000 ER visits a year in the U.S..
If tests for warfarin-sensitivity genes become commonplace, it would encourage other efforts to develop genetic tests linked to popular drugs. Researchers are looking at how genes affect the action of such drugs as the antidepressant Prozac, the diabetes drug metformin and the asthma inhaler albuterol. A team of Harvard researchers has shown good results with a genetic test predicting who will fail to respond to albuterol and similar drugs, says Scott Weiss, a professor involved in the study.
"There's going to be a debate about every one of these tests," says Dr. Weiss.
Researchers began developing warfarin as a drug for people after an Army inductee during the Korean War tried to commit suicide by eating it. He survived, and doctors were struck by how effectively the poison had restricted his blood's clotting ability, or coagulation. President Eisenhower took it after a 1955 heart attack. The drug's generic name derives from the Wisconsin Alumni Research Foundation, or WARF, which originally held the patent on it. It is also known by the brand name Coumadin.
From the start, doctors struggled with how to give warfarin safely. In the 1990s, they began using a measure called International Normalized Ratio that compares the blood's clotting ability at a given moment to a standardized measure. Typically, doctors prescribe an initial warfarin dose based on factors including a patient's size, age and other medications. They check the patient's blood frequently -- every few days, at first -- and tweak the dose to bring the INR within the desired range.
(Something similar to Warfarin- see below!)
DNAPrint published in Pharmacogenetics and Genomics
http://www.jpharmacogenetics.com/pt/re/pharmgen/currenttoc.htm;jsessionid=GGMdwC31xTF4QW0HpvJ8nyySTl....
CYP2D6*4 polymorphism is associated with statin-induced muscle effects.
ORIGINAL ARTICLES
Pharmacogenetics & Genomics. 17(9):695-707, September 2007.
Frudakis, Tony N.; Thomas, Matthew J.; Ginjupalli, Siva N.; Handelin, Barbara; Gabriel, Richard; Gomez, Hector J.
Abstract:
Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena.
--------------like this below!!!
FDA Pushes Genetic Test Tied to Warfarin
[Doctors worry about malpractice liability if the test is not performed.]words from Dew Diligence.
http://online.wsj.com/article/SB118722561330199147.html
By ANNA WILDE MATHEWS
August 16, 2007
In May, Karen Schmale was rushed to Barnes-Jewish Hospital in St. Louis, gasping for air. Diagnosed with blood clots in her lungs, she was given a powerful blood thinner called warfarin.
The medicine probably helped save her life. Then it almost killed her. About a week later, Ms. Schmale, 49 years old, noticed blood in her urine and soon became so weak she could barely climb the stairs to her second-floor apartment. The warfarin was causing the bleeding, and she had to go back to the hospital for an emergency blood transfusion.
A genetic test revealed Ms. Schmale was unusually sensitive to the drug and needed a smaller dose. Before the test, "nobody knew I was going to react like that," says Ms. Schmale, a data-entry coordinator at a university in St. Louis.
The case shows the advances in personalized medicine, where treatment is tailored to an individual's genetic makeup. But, in a possible harbinger of battles to come, the warfarin tests have also led to a clash between the Food and Drug Administration and some doctors.
The FDA is set to announce today that warfarin's label will carry new information describing the role of genetics in dosing. The label will say that a lower initial warfarin dose "should be considered for patients with certain genetic variations."
Some specialists say testing hasn't been proved to reduce the risks of the drug. They fear patients who don't get the tests and run into trouble will sue doctors, citing the drug's label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don't. The insurers say they need more evidence about the benefits.
"It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label," said University of Washington professor Ann Wittkowsky in an interview before the FDA's decision. "It is fascinating science, but it is not yet ready for prime time."
Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has "substantial" evidence to support the new label and hopes it will improve safety by informing doctors.
Dr. Lesko is part of a larger initiative at the FDA to promote the use of genetic factors to predict how individuals will react to medicines. It's a shift for the agency, which traditionally has more of a reactive role as the regulator of the drug industry. "If the potential wasn't huge, we wouldn't be doing it," he says. "We felt we had to be more outspoken."
The agency has already included information about genetic testing on the labels of less-frequently used drugs for colon cancer and leukemia, among others. One drug, Genentech Inc.'s Herceptin for breast cancer, is designed especially for women whose tumor cells have a genetic abnormality.
But warfarin is the largest case study to date of what happens when the new science of genetics runs up against the everyday practice of medicine. Originally marketed as a rat poison, the drug was prescribed more than 30 million times last year in the U.S., according to IMS Health. It's available as an inexpensive generic pill.
Its main problem is the narrow window for safety. An excessive dose leads to bleeding. Warfarin is the second-most-likely drug, after insulin, to send Americans to the emergency room. By one estimate, it accounts for 43,000 ER visits a year in the U.S..
If tests for warfarin-sensitivity genes become commonplace, it would encourage other efforts to develop genetic tests linked to popular drugs. Researchers are looking at how genes affect the action of such drugs as the antidepressant Prozac, the diabetes drug metformin and the asthma inhaler albuterol. A team of Harvard researchers has shown good results with a genetic test predicting who will fail to respond to albuterol and similar drugs, says Scott Weiss, a professor involved in the study.
"There's going to be a debate about every one of these tests," says Dr. Weiss.
Researchers began developing warfarin as a drug for people after an Army inductee during the Korean War tried to commit suicide by eating it. He survived, and doctors were struck by how effectively the poison had restricted his blood's clotting ability, or coagulation. President Eisenhower took it after a 1955 heart attack. The drug's generic name derives from the Wisconsin Alumni Research Foundation, or WARF, which originally held the patent on it. It is also known by the brand name Coumadin.
From the start, doctors struggled with how to give warfarin safely. In the 1990s, they began using a measure called International Normalized Ratio that compares the blood's clotting ability at a given moment to a standardized measure. Typically, doctors prescribe an initial warfarin dose based on factors including a patient's size, age and other medications. They check the patient's blood frequently -- every few days, at first -- and tweak the dose to bring the INR within the desired range.
