Ray Symposium
Everyone is unique, down to their DNA. Because of these genetic differences, the same drug therapy does not have the same effect on everyone. By taking into consideration a person’s genetic makeup, health care providers can help maximize effectiveness and reduce harmful effects by choosing drugs and dosages that fit the individual.
William E. Evans, PharmD, Director and Chief Executive Officer of St. Jude Children’s Research Hospital, talked about pharmacogenomics at the fifth annual Ray Symposium at Western University of Health Sciences April 21, 2011.
The Ray Symposium is organized by the College of Pharmacy in honor of Max Ray, MS, PharmD, Dean Emeritus of the College of Pharmacy. He joined WesternU as Professor of Pharmacy Practice and Director of the Center for Pharmacy Practice and Development in 1996, and served as Dean of the College of Pharmacy from 1999 to 2006. The Ray Symposium is sponsored by McKesson Pharmaceutical.
Pharmacogenomics looks at how genetics and inheritance affect drug metabolism and drug response, Evans said. If you take 50 people with leukemia and give them all the same drug therapy, not all patients will respond the same. For some, the treatment will not have the desired effect. Others will have adverse drug effects and develop toxicity from the treatment.
“At the very center of all of these things that happen to our patients is their DNA, their genetic constitution,” Evans said. “It is who they are that they inherited from our parents.”
Leukemia patients at St. Jude are treated with the medication 6-mercaptopurine. The enzyme thiopurine methyltransferase (TPMT) metabolizes this drug. About 90 percent of the population has high activity of this enzyme, about 10 percent have intermediate activity and 1 in 300 have low activity or no activity, Evans said.
“Our patients need this enzyme to get rid of this drug,” he said. “It is used to treat leukemia, but it also kills normal cells if the levels get too high.”
Evans and his colleagues developed a diagnostic test to identify patients who were deficient in TPMT.
“The reason we wanted to know this was the kid who lacks this enzyme can’t get rid of the drug, and they have 10 times more active drug in their blood then kids that have normal activity of this enzyme,” Evans said.
Ten percent of the population is at risk of toxicity if they receive the standard dose of the drug, he said.
“Based on that information, we have completely changed the way we prescribe this drug,” Evans said. “We used to give everybody who walked through the door the same dose of mercaptopurine. We had wildly different levels of active drug in their blood, and markedly different risk of toxicity.”
Today, they test patients for TPMT activity levels before they begin treatment for leukemia. If they don’t have a good copy of the enzyme, they receive 10 percent of the standard dose.
“Once we do this, we have exactly the same risk of toxicity across the entire population, and the risk of relapse is not different among those different phenotypes,” Evans said.
Evans envisions a day when all research is combined to form a genetic map for effective treatments.
“If we do these diagnostic tests and we put them in a secure database, and only the patient can authorize their health care provider to look at it, then we can do those tests very cheaply and use it for the rest of that patient’s life,” Evans said. “So the day may come when mom and dad go home with the new baby and the baby’s genome. The baby’s genome can be deposited electronically in a secure database. For every treatment decision for that patient for the rest of their life, that data is going to be available to make smarter decisions, and it’s going to be used by all health care providers.
“We’re going to start moving away from that empirical model … where every patient with hypertension or leukemia is put in the same box,” he said. “We’re going to start subdividing them based on their ability to respond to drugs, based on genetics.”
Why isn’t this already being done? According to Evans, the medical community remains skeptical and has not embraced it because genetics sound complicated.
“It doesn’t have to be. Going forward, part of our challenge as professionals is to take some of the complication out of it, take some of the mystique out of genetics,” he said. “It is true you cannot expect every practicing health care professional to be able to interpret DNA sequence and make a decision about drug therapy. That’s not what they do.”
He compared pharmacogenomics to the bar code on a tomato sauce can. Most people don’t know how much a can costs just by looking at the bar code. But when you run it through a scanner, the price appears.
“So that is what has to happen with pharmacogenetics,” Evans said. “We’re going to have to have the readout, which is going to translate this DNA sequence to a readout of the genotype. And the input is going to be: I have new diagnostic, a new case of high blood pressure or a new case of leukemia. I have that patient’s genome. So based on that provisional diagnosis, and the list of drugs I can choose from, it’s going tell me the genotypes that patient has and whether they can respond to clopidogrel, or not or whether need to start a higher or lower dose of morphine. That’s going to be outcome. There’s still going to be a lot of thinking that has to happen after that by the pharmacist, by the physician, by the nurse, but it’s not going to be that complicated in terms of the readout.”
College of Pharmacy Dean Daniel Robinson, PharmD, noted that moving from a survival rate of 35 percent to 90 percent in acute lymphoblastic leukemia in children – which is what St. Jude has accomplished — was done without a single new drug.
“There’s no magic drug, it’s how we are using the drug appropriately – the right drug in the right situation, in the right dose,” Robinson said. “If we just use our pharmaceutical products more intelligently, we can achieve a lot more.”
