VITALResearch
Perfecting Precision Prescribing
Research by Drs. Rolf Kreutz and David Flockhart is changing the way medications are prescribed.
Take a look in your medicine cabinet. How much do you know about the medications inside?
In fact, how much does anyone really know about how the pills we ingest wend their way through our bodies and work their wonders? Not enough, it turns out.
But a team of physicians and scientists at the Indiana University School of Medicine is taking a leading role in discovering more about how some commonly used drugs work and how an individual’s genes affect the response. What they’re learning is already helping patients avoid sometimes serious side effects and transforming the way medications are prescribed for diseases ranging from cancer to AIDS to heart attacks.
“What’s become clear recently is that medications meant to bring about a beneficial effect in patients also bring about the opposite,” says David Flockhart, MD, PhD, director of clinical pharmacology at the School of Medicine and an internationally recognized expert in the field. “Some people get hurt—opposite of better—when they take the medication. We would love to know in advance if you’re someone who is going to be helped or hurt.”
To find the answers, Dr. Flockhart and colleagues from a variety of specialties are looking closely at how an individual’s genetic makeup and other factors, including drug interactions, affect our responses to medications. The implications are huge.
Consider Plavix, a blood thinner that is one of the world’s top selling drugs.
Plavix prevents blood clots and is commonly prescribed to patients who have had stents implanted to open blocked arteries. But researchers found that it isn’t always effective, in part because the enzyme necessary to metabolize the drug into its active form doesn’t work in everyone.
But a faulty enzyme seemed only part of the explanation. Even in people with fully functioning enzymes, the medication wasn’t always as effective as expected. So researchers around the country—including Dr. Flockhart and Rolf Kreutz, MD, a fellow at the Krannert Institute of Cardiology—began looking for more explanations.
The culprit, they found, was a class of stomach acid reducers called proton pump inhibitors, commonly known by the brand names Prilosec, Nexium, Protonix and Prevacid. It turns out, the body uses the same enzyme to metabolize both the acid reducers and Plavix, so processing one can interfere with the ability to handle the other. Ironically, doctors often prescribe the two together.
In a retrospective study of more than 16,000 patients—one of the largest conducted—the School of Medicine researchers found that those taking this specific class of acid reducers with Plavix increased their risk of a repeat heart attack, stroke or other cardiovascular problems by more than 50 percent, compared to those taking Plavix alone.
As a result of those findings and similar conclusions from investigators elsewhere, the FDA in November warned against taking the drugs together.
“More and more we are realizing that the drugs we use and think work probably do in a majority of people but not in everyone,” Dr. Kreutz says. “There’s hardly a drug that has a uniform effect on every person. We want to figure out beforehand how medications will behave in each person so we can tailor drugs to the individual patient.”
Cancer drugs provide another telling example.
Dr. Flockhart is a well-respected authority on the drug tamoxifen, a widely used treatment to prevent the recurrence of breast cancers that are estrogen-dependent.
Over the last decade or so, Dr. Flockhart and his collaborators have shed light on the way the body metabolizes tamoxifen. In doing so, they have revealed that some women’s genes prevent them from processing the drug effectively. In other words, the drug just doesn’t help them, and they need to take something else to get results.
While patients certainly can’t control their genes, it turns out other factors that influence the effectiveness of tamoxifen can be controlled.
For example, Dr. Flockhart found that certain antidepressants commonly taken to alleviate side effects from breast cancer treatment interfere with tamoxifen. A study released last year by the IU School of Medicine and Medco Health Solutions found that taking both medications together can more than double the risk of breast cancer recurrence. The FDA has since started warning doctors about the risk.
Dr. Flockhart is the holder of the Harry and Edith Gladstein Chair in Cancer Epidemiology and Genetics. Because the chair is endowed, it produces income each year that provides vital support for his research. Andy Gladstein, son of the late Harry and Edith Gladstein, said he and his wife, Marylynn, are motivated by the idea of “helping people in pain.”
Dr. Flockhart believes genetics and “precision prescribing” are key to helping patients affected by cancer and myriad other diseases, as well.
“The biggest thing over the next few years is going to be the introduction of genetic testing into the broad marketplace,” Dr. Flockhart predicts. “Eventually it’s going to be something that’s done at birth before you ever get any medications.”
And the IU School of Medicine will no doubt be playing a leading role.
