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Genetics Improves Some Warfarin Dosing; Clinical Trials Next

NEW YORK (GenomeWeb News) – Combining genetic and clinical information can significantly improve warfarin dose predictions for individuals who need high or low doses of the drug, according to a paper appearing in today's issue of the New England Journal of Medicine.

Coming on the heels of these results, the National Institutes of Health in the US and universities in the UK announced that they are planning clinical trials to determine whether incorporating genetics into warfarin dosing will improve patient outcomes.

The International Warfarin Pharmacogenetics Consortium used data from 4,043 individuals whose warfarin dose had been stabilized and used this information to develop a pharmacogenetic algorithm. When they tested their algorithm in the original group and a validation group of more than 1,000 additional patients, the team found that a pharmacogenetics-based method was better for predicting stable doses in the high and low-dose warfarin groups than either clinical data alone or a fixed-dose approach.

"We found that even just including demographic and clinical information, such as the patient's height, weight, ethnic background, and other medications, yielded initial doses that were closer to the final, ideal dose, than the standard, 'fixed-dose' regimen," principal investigator Russ Altman, chair of Stanford University School of Medicine's bioengineering department, said in a statement. "But including the genetic data enabled us to be much more accurate."

The consortium — which involved researchers from 21 participating research groups in Taiwan, Japan, Korea, Singapore, Sweden, Israel, Brazil, the UK, and the US — tested three different dosing strategies using data from 4,043 individuals whose optimal warfarin doses had been established through trial and error. The first dosing method was based on clinical data, the second on clinical and genetic information (specifically, two CYP2C9 and seven VKORC1 polymorphisms), and the third was a fixed warfarin dose approach.

The researchers subsequently tested how well each approach predicted the actual stable warfarin dose in the test group and a validation cohort of 1,009 individuals.

Their results suggest that the pharmacogenetic algorithms predicted warfarin doses closer to individuals' stable dose than the other two approaches — particularly for the 46 percent of individuals taking high doses of warfarin (49 milligrams each week or more) and those taking the lowest warfarin doses (21 milligrams or less per week).

"These are the patients for whom an under-dose or an over-dose could have adverse clinical consequences," the authors wrote. "Patients who require intermediate doses are likely to obtain little benefit from the use of a pharmacogenetic algorithm."

In an editorial accompanying the NEJM paper, Janet Woodcock and Lawrence Lesko, from the US Food and Drug Administration's Center for Drug Evaluation and Research, noted that pharmacogenetics is starting to address individual variability in ways that traditional randomized, controlled trials couldn't. "Pharmacogenetics has the potential to increase benefit and reduce harm in people whose drug responses are not 'average,'" Woodcock and Lesko wrote.

The duo also argued that the "evidence base for pharmacogenetic testing should be informed by the pharmacologic characteristics of the drug and the characteristics of the outliers."

Altman and his co-workers plan to tweak the algorithm based on information from an ongoing study of about 100 Stanford Anticoagulation Clinic patients in the Bay Area. The current pharmacogenetics algorithm and data used to derive it will be made available via the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmaGKB), a database managed by researchers at Stanford.

While they say their algorithm "provides a robust basis for a prospective clinical trial of the efficacy of genetically informed dose estimation for patients who require warfarin," the authors cautioned that it doesn't provide information about whether improved dosing in the high and low dose groups will improve clinical outcomes.

To address this issue, the NIH, which helped support the latest study, is planning to launch a large prospective, multi-center, randomized clinical trial in the US next month. The "Clarification of Optimal Anticoagulation through Genetics" will enroll 1,200 participants at a dozen clinical sites.

Meanwhile, researchers at Newcastle University and the University of Liverpool are leading a European clinical trial involving 13 research centers in seven countries. Researchers there expect to enroll 2,700 individuals who are starting treatment with either warfarin or other anticoagulants, such as acenocoumarol and phenprocoumon.

And beyond the implications for warfarin use, some involved with the NEJM study say their results suggest genetics could improve dosing for other drugs too. For instance, Altman and others are also participating in the International Tamoxifen Pharmacogenomics Consortium, aimed at assessing the influence of CYP2D9 genotype, if any, on treatment with the breast cancer drug tamoxifen.

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