Optimal drug dose of common anticoagulant

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Genetic testing can be used to help personalize the therapeutic dosage of warfarin, a commonly-used anticoagulant, as per research reported in the September 1, 2007, issue of Blood, the journal of the American Society of Hematology. This result represents one of the first applications of using an individuals genetic information to guide personal medical care.

Because individuals metabolize drugs differently, varying doses of warfarin are needed for the drug to be effective in each patient. Too much warfarin can cause severe bleeding, and too little can cause dangerous blood clots. Currently, there is little guidance for predicting how much of the drug a person will need. Physicians have had to roughly estimate an initial dose of warfarin and then continually monitor a patients International Normalized Ratio (INR) value (a measure of how fast the blood clots), during therapy to tweak the dosage by trial and error.

For the first time, a group of St. Louis scientists combined the standard INR method with genetic testing to predict the therapeutic warfarin dose. Since warfarin is often prescribed after major orthopedic surgery to prevent blood clots in the legs, the study followed 92 adults undergoing either total hip or knee replacement at the Washington University Medical Center, who had never previously taken the anticoagulant.

Previous to warfarin therapy, the scientists collected blood samples and each patients medical history. The blood tests were used to examine variations in two genes, CYP2C9 and VKORC1, that may affect warfarin dosing. Variants in CYP2C9 impair the bodys breakdown of warfarin; variants in VKORC1 cause increased warfarin sensitivity. The patients were assigned initial doses of warfarin based on clinical factors and their genotype. The scientists followed the patients until successful therapy outcomes were achieved several weeks later.

By combining variants in these genes with initial INR response and other clinical factors, the scientists derived a dosing equation that estimated the therapeutic warfarin dose. The scientists observed that these two genes were important in predicting the response to warfarin. Additional factors, such as blood loss during surgery and smoking status, also correlated with therapeutic dose.

Using these data, the scientists developed a therapeutic model that could be used by physicians to refine warfarin dosage with greater accuracy than clinical factors alone. The scientists have made this dosing model publicly available on a free Web site, www.warfarindosing.org, and are now validating it in orthopedic and non-orthopedic patients beginning warfarin treatment.

If validated, especially in patients taking warfarin for reasons other than orthopedic surgery, such as to prevent stroke, this gene-based dosing could predict a safe and effective warfarin dose at the start of therapy, thus minimizing the risks of the current trial-and-error approach.


Posted by: Daniel    Source