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UNC Professor Outlines Accomplishments and Challenges of Personalized Medicine

By Eddy Ball
July 2007

Howard McLeod
McLeod's enthusiasm was obvious as he described how pharmacogenetic research has increased understanding of the drugs warfarin and tamoxifen. (Photo courtesy of Steve McCaw)

Stephanie London
Among the scientists who turned out for McLeod's lecture was Epidemiologist Stephanie London, M.D. (Photo courtesy of Steve McCaw)

Darryl Zeldin
Host Darryl Zeldin monitored questions from the audience following the lecture. (Photo courtesy of Steve McCaw)

With an impressive grasp of the topic and a healthy infusion of wit and stand-up timing, Howard McLeod, PharmD., kept the audience attentive - and amused - during his June 15 lecture in Rodbell Auditorium. McLeod's talk, titled "Drugs and the Genome: Will it Really Improve Therapy?" was part of the Institute's Frontiers of Environmental Sciences series and was hosted by Senior Scientist Darryl Zeldin, M.D.

McLeod is the Fred N. Eshelman Distinguished Professor and Director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill. He also holds appointments in the Schools of Pharmacy and Medicine, as well as the Lineberger Comprehensive Cancer Center.

McLeod opened his talk by introducing the theme he would develop in the lecture - "trying to make the genome useful to grandma" through research with specific applications in the clinical treatment of illnesses. "We have medicines that benefit many people, but we don't know enough about them to really choose medicines carefully," he explained, "and so understanding mechanisms is really key to achieving this goal of individualized therapy."

According to McLeod, the abundance of FDA-approved drugs for common illnesses, such as colon cancer and hypertension, has made choosing the right medication for an individual patient even more important. Medicine needs to replace the current paradigm of relying on a uniform therapy and dealing afterwards with the patients who do not respond or respond with unacceptable levels of toxicity. Pharmacogenetics, McLeod argued, offers a way to understand an important part of why patients respond differently to the same medication.

To illustrate the potential of integrated pharmacogenetic research, McLeod turned to the case of the very commonly prescribed anti-coagulant drug warfarin. Currently used with over two million patients, this inexpensive drug has a large variability in dosing among patients. Warfarin, he said, is a drug that "costs pennies in terms of the actual pill, but thousands in terms of patient management."

Identifying variability in specific genes that affect detoxification of the drug and the enzyme controlling vitamin K metabolism has allowed clinicians to understand better the influence of genetic factors on the way patients respond to the medication. "This was highlighting to us for one of the first times in clinical medicine how pharmacokinetic variability and pharmacodynamic variability at the gene level come together to explain, in this case, the dose for warfarin for patients," McLeod said.

The results this pharmacogenetic breakthrough led the Food and Drug Administration to consider changing the warfarin package insert to include genetic information as part of the risk identification for warfarin. Physicians can now take advantage of a web site(http://www.warfarindosing.org/)Iwasaspan Exit NIEHS supported by the Barnes-Jewish Hospital at Washington University Medical Center, the NIH and other donors for guidance in determining the best dose for their patients.

Along with its effects on safe and effective treatment, individualized medicine also has financial implications - and physicians, insurance companies and malpractice attorneys are now paying attention to them. For example, physicians are painfully aware of the added burden of treating patients who fail to respond to uniform therapies, and payers are looking to genetics as a way of justifying more expensive treatments for breast cancer patients as an alternative to the drug tamoxifen.

McLeod emphasized that there are still many challenges and questions to be answered, and much more discovery work needs to be done to find the right biomarkers. Physician attitudes need to change, and patients need to demand more real personalized medicine. Still, important advances, especially from large clinical trials now underway, are taking place to give researchers improved access to the robust data sets they need.

"Genetics will be a contributor to better medical decision making," McLeod concluded. "It will not be the [only] source of better decision making....[but] we're now actually able to go and do intervention."



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