Scientists Link Genetics to Warfarin Pharmacokinetics

Stanford University scientists have been crunching patient information from a number of clinics that looked at how people respond to various doses of warfarin (Coumadin), an anticoagulant known to most of our readers. Using additional genetic information gathered from the study participants, scientists were able to find a genetic pharmacokinetic marker that might help clinicians one day to optimize this drug’s dosage for their patients. The benefits of this research are tremendous: patients having too much of Coumadin on board risk bleeding and strokes; take too little of this drug, and risk throwing some unwanted emboli.
From Stanford Med press release:

Altman, who chairs Stanford’s bioengineering department, and Teri Klein, PhD, a senior research scientist in genetics at the School of Medicine, solicited, in collaboration with others, warfarin dose-response information from over 21 sites — known as the International Warfarin Pharmacogenetics Consortium — in nine countries for inclusion in the study, which was published in the Feb. 19 issue of the New England Journal of Medicine.
Although this study is not the first to show the advantage of incorporating genetic information into prescribing patterns, it is by far the largest and most inclusive: It includes information on more than 5,000 patients from many ethnic groups. Members of the consortium are currently working to design a clinical trial to confirm the results of this prospective study.
“This research study has made an important advance toward personalizing medicine — it uses data from countries around the world to develop a gene-based strategy for warfarin dosing that could benefit a wide range of patients,” said Jeremy Berg, PhD, director of the National Institute of General Medical Sciences. “This is a wonderful example of international cooperation and the results are especially valuable for the United States, since our population is so genetically diverse.”
Altman, Klein, Stanford medical student Hersh Sagreiya and members of the consortium collected a variety of demographic, clinical and genetic information from patients at risk for stroke, heart disease or other blood clotting problems for whom the ideal doses of warfarin had already been established by trial and error. In particular, they determined which version of each of two genes was carried by each patient. One, called CYP2C9, affects how the liver activates and excretes warfarin. The other, called VKORC1, activates vitamin K, which is essential for blood clotting.
They combined this information with the pre-determined ideal warfarin dose in about 4,000 patients and used it to develop a computerized dose-prediction algorithm. They then tested the new algorithm with and without the genetic data on the remaining 1,000 or so patients.
“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,” said Altman. “But including the genetic data enabled us to be much more accurate.”
Specifically, this pharmacogenetic algorithm yielded predictions that were, on average, within about 8.5 mg/week of the patient’s ideal dose; using just the demographic and clinical data predicted doses that were within about 10 mg of the ideal weekly dose. In contrast, starting every patient on 35 mg/week as part of the more standard fixed-dose approach gave an average error of about 13 mg. The algorithm and the data used to derive it will be publicly available on the Stanford-managed Pharmacogenetics and Pharmacogenomics Knowledge Base after the study is published.

Video of Stanford researchers explaining their work: