Pharmacogenetics

One of the fundamental truths of medicine is that no two patients are alike. Every case presents with a distinctive combination of symptoms and history, determined in large part by each patient's genetic make-up, and doctors must carefully tailor their care to ensure the best results.

This genetic variability affects a broad range of medical considerations, but arguably one of the most important is drug sensitivity. Physicians have known for at least 20 years that people metabolize drugs differently based upon genetic factors, says Roland Valdes Jr., Ph.D., senior vice chair for the Department of Pathology and Laboratory Medicine at the University of Louisville.

Those metabolic differences often make it challenging for physicians to determine proper dosage levels based on the "one-size-fits-all" guidelines offered by pharmaceutical companies, he says.

Some patients metabolize drugs so rapidly, for example, that the pharmacological agents don't remain in the body long enough to achieve the desired effect -- unless dosage levels are increased. Other patients might metabolize the same drug so slowly it accumulates to toxic levels and causes symptoms of overdose -- unless dosage levels are decreased.

Then there are people who might not respond to a certain class of drugs at all, or they may suffer adverse reactions no matter what dose is prescribed.

"There is clear evidence that these kinds of adverse drug reactions are a concern," Valdes says. "They cause more than 100,000 deaths every year in the United States alone, and another 2.2 million people need hospitalization for treatment related to overdoses. The problem is costing our health-care system billions of dollars annually."

It wasn't until the human genome was fully decoded in the late 1990s, however, that scientists could identify genetic variations responsible for differences in drug uptake.

Since then, researchers at UofL and elsewhere have identified a handful of deviations responsible for the majority of drug sensitivities, opening the door for patient-specific information that can help physicians customize drug dosages and improve patient care.

This new field of study -- called pharmacogenetics, for its combination of pharmacology and genetics -- is so promising that Valdes and UofL pathology professor Mark Linder, Ph.D., have formed the University of Louisville Pharmacogenetics Diagnostic Laboratory to promote its adoption.

With the help of start-up funding provided by the School of Medicine, Valdes founded the lab in 2000 as part of a broader pharmacogenetics program at the university. It initially focused on basic research, thanks in part to a $1.5 million grant from the National Institutes of Health, but quickly grew to include limited clinical services.

By early 2003, Valdes and Linder decided it was time to begin full-scale clinical testing, and they opened the lab's pharmacogenetic services to any physician willing to pay the testing fees, which currently range from $125 to $250. Now, anyone can have his or her DNA analyzed for a wide variety of unique drug sensitivities.

The lab's growth has been remarkable, climbing from a handful of DNA tests each month initially to several hundred per month now, says Valdes, who serves as the facility's director.

The UofL lab is one of less than a half-dozen pharmacogenetics -- or PGx -- laboratories nationwide, and it is the only one in the United States to offer screening services for a broad range of common drugs, Linder notes.

To accommodate future growth, Valdes and Linder have partnered with a national laboratory corporation to form a Louisville-based company that will focus on clinical pharmacogenetic testing.

The company will boast state-of-the-art lab space capable of processing several thousand samples per month, Valdes says, and should begin operations later this year. It will be located in downtown Louisville's Metacyte facility, a biomedical business incubator whose operation is funded in part by the Louisville Medical Center Development Corp.

"I think we're approaching a new day in medicine," Valdes says. "The work we're doing now will help physicians fine-tune certain medications and really make (dosing) something that is individualized for each patient."

Toni Miles, M.D., Ph.D., agrees.

Miles, who holds the Ole A., Mable Wise and Wilma Wise Nelson Chair in Clinical Geriatrics Research at UofL, says the potential impact of PGx testing is "comparable to the introduction of routine antibiotics in health care."

"Right now, doctors have to go through a sequence of trial and error to match a patient with the most effective medication and dosage," Miles explains.

"That is, we give the person one drug from the class of drugs needed, and if that doesn't work well or makes the patient sick, we try something else."

But pharmacogenetic testing could put an end to much of that, says Miles, who is working with a network of primary care physicians to explore the application of PGx technology in everyday practice.

"PGx testing offers several benefits to patients," Miles says. "First, the process makes prescribing safer. Doctors won't be in the position of mistakenly giving a medication to someone who would be injured by the medicine.

"Second, the correct drug at the proper dose would get to the patient sooner. This should decrease the amount of time a person feels the effects of his or her illness.

"Third, the trial-and-error process is costly. We could adopt a strategy of starting with the least expensive medication and working from there."

Looking for enzymes

Pharmacogenetic testing begins with a small blood sample or a cotton swab of tissue taken from the inside of a patient's cheek.

UofL technologists conduct a DNA analysis of the sample, looking for well-known genetic variations that affect the body's production of key drug-metabolizing enzymes.

The enzymes under scrutiny are responsible for metabolizing about 50 to 60 percent of the drugs prescribed today, Valdes says.

One type of enzyme variant might make a patient an ultra-rapid metabolizer of Paxil who requires higher drug dosages to achieve the desired effect, while another variant of the same enzyme could make a patient a poor metabolizer of Prozac who will become toxically hypersensitive to the drug unless the dosage is lowered.

Once the laboratory analysis is complete, a detailed report is compiled for the physician who requested the test.

That report, in conjunction with the lab's information-packed Web site, sets the UofL operation apart from other PGx services around the country, says Kristen Reynolds, Ph.D., acting director of laboratory operations.

"We really try to give physicians as much consulting and interpretive guidance as possible, so they know what to do with the information in the report," Reynolds says. "No one else provides that level of service."

PGx screenings can be especially useful to physicians prescribing anticoagulants like Coumadin or anticonvulsants like Dilantin, both of which require fairly precise dosing to be effective.

"You can overdose very easily with Coumadin, and then the patient may suffer a cranial hemorrhage or stroke," says Linder, the lab's associate director.

"Dilantin is an anticonvulsant, but it can induce seizures if the dosage is too high. These two drugs have a narrow therapeutic index and are difficult to dose properly, especially when you introduce genetic variability between patients."

Linder notes that about 35 percent of the population has a genetic deficiency affecting the enzyme responsible for metabolizing Coumadin and Dilantin -- CYP2C9.

The lab also screens for variations in several other enzymes, including CYP2C19, which metabolizes antacids like Prilosec and Prevacid; and CYP2D6, which metabolizes one fourth of all prescription drugs, including Abilify, Allegra, Claritin, codiene, Mellaril, Oxycontin, Paxil, Prozac and Staterra.

Approximately 10 percent of the population has a slow-acting form of 2D6, while 7 percent are ultra-rapid metabolizers with a "super-fast-acting form" of the enzyme, Linder says.

These kinds of genetic profiles represent a major advance over previous methods of assessing metabolism, which included a process known as phenotyping that measured a drug's byproducts in urine, Linder says.

"The problem with phenotyping -- the reason it was never really accepted -- was that it required too much intervention," Linder explains.

"The physician had to administer a dose, and the patient had to stay at the doctor's office for eight hours before giving a urine sample. With our process, a doctor scrapes the inside of a patient's cheek and sticks the swab in the mail."

UofL's laboratory also supports clinical trials of new medications, identifies individuals to participate in drug studies and researches new target genes, Valdes says.

Poised for growth

Valdes sees a bright future for pharmacogenetics.

In addition to helping physicians determine appropriate dosages for specific drugs, UofL's PGx lab can determine if a patient would be better off taking an entirely different class of drugs to treat a specific malady.

That concept eventually could expand to the point where pharmaceutical companies create classes of medicines targeted at subsets of people with unique genetic profiles, rather than developing drugs intended for everyone, Valdes says.

It also might mean the re-introduction of certain drugs that were pulled from the market because they were toxic to some people, even though they were effective for others.

This would, of course, require PGx testing for every patient -- a possibility Valdes doesn't rule out.

"I think we're heading in that direction, but it may take 10 years before we get there," says Valdes, who along with Linder has been driving the field of pharmacogenetics forward ever since the two co-authored a landmark 
paper in 1998 elucidating the clinical potential of PGx.

"We'll have to do two things first: We'll have to show that, in fact, these specific analyses are very strongly linked to the outcome; and we'll have to demonstrate that it's economically feasible to screen everybody before they take medication."

In the meantime, UofL will continue its leading role in the field of pharmacogenetics.

Valdes currently is chairing a national committee to draft practice guidelines for clinical laboratories that conduct PGx testing. The guidelines, which are being developed under the sponsorship of the National Academy of Clinical Biochemistry, also will assist physicians in the proper use of PGx test results. Linder serves on the same committee.

"I think pharmacogenetic screening will eventually bring a different perspective to the field of medicine," Valdes says. "It's a personalized perspective, where physicians will be able to look at your profile and know that one particular kind of therapeutic is better for you than the other type," he says.

"It's an important perspective, and I think it will drive the future of medical practice."