Genetics

What’s Your Metabolizer Rate?

The speed at which bodies process medications can vary widely, and determining each patient’s status is becoming crucial in fighting chronic disease.

By Turna Ray featured image

When Alissa Tschetter-Siedschlaw rushed her adopted daughter into the emergency room at the Blank Children’s Hospital in Des Moines, Iowa, last year, 13-year-old Madilyn had a 10 percent chance of survival. Luckily, she was able to hand the nurse a card that listed Madilyn’s metabolizer status for a handful of enzymes that the body uses to process the majority of drugs. Tschetter-Siedschlaw believes this card may have saved her child’s life.

Since birth, Madilyn has suffered from a litany of health issues. Three months premature, Madilyn was also affected by alcohol and methamphetamines. Her brain was swollen, retaining fluid, and bleeding, and she had trouble with her eyesight and lung function. As she grew, Madilyn struggled with severe mental illness. Doctors have diagnosed her with psychotic disorder, attention deficit hyperactivity disorder, and intermittent explosive disorder ─ during bouts of which she displays violent or aggressive behavior.

After taking Madilyn to doctors for every conceivable specialty, from pediatric neurosurgeons to chiropractors, “I was at my wit’s end trying to help her,” Tschetter-Siedschlaw says. “She obviously wasn’t responding to her meds. She was taking crazy doses of antipsychotics as a kid that would usually be prescribed to a male adult with psychosis, and it would be like water to her.”

When a nurse at a neurotherapy session told Tschetter-Siedschlaw that Madilyn could be tested to see if she would respond better to some medications than others, she acted immediately. With the help of a healthcare provider, Tschetter-Siedschlaw filled out a risk-assessment questionnaire for Madilyn, recording the drugs she was on and her health conditions. She took a smattering of cells from the inside of Madilyn’s cheek with a swab and sent the sample and questionnaire to a company called Genelex.

A few weeks later, Tschetter-Siedschlaw received test results detailing the top medications her daughter would metabolize well or poorly, as well as the drugs that might interact if prescribed together and cause ill effects in Madilyn. She also received a card that noted Madilyn was a normal metabolizer of the CYP2D6 and CYP2C9 enzymes, as well as an ultra-rapid metabolizer of CYP2C19.

The codes listed on Madilyn’s card describe enzymes in the so-called cytochrome P450 (CYP450) superfamily of enzymes, which play a crucial role in the body’s ability to process medications. Particularly, six CYP450 enzymes — CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 — are responsible for metabolizing 90 percent of drugs. However, when patients have variations — called polymorphisms — in the genes that code for these enzymes, this can speed up or slow down their ability to process or activate certain drugs.

For example, if a particular CYP450 variation makes someone a rapid metabolizer of a drug, he or she may process it so fast that the drug won’t have a chance to reach optimal blood levels, leading to limited amounts of drug that can act on the patient’s system. Meanwhile, in a poor metabolizer, the drug can build up in the body to toxic levels and cause treatment-related adverse reactions. For patients with abnormal CYP450 metabolizer status, sometimes doctors need to adjust the standard dose of a drug or administer a different medication.

Specific therapies can be CYP450 inducers or inhibitors, meaning when patients take these drugs with certain other medications, they don’t interact well together. Drugs that are CYP450 inducers ramp up, and inhibitors hinder patients’ ability to metabolize or activate other medications. Given that 29 percent of Americans are taking five or more medications at one time, these CYP450-mediated interactions between drugs place patients at risk for adverse events. According to data collected by Genelex, the company that tested Madilyn’s drug metabolizer status, approximately 85 percent of patients have at least one CYP450 marker that makes them unable to metabolize drugs normally.

A week after receiving the test results, Madilyn ended up in the ICU with a severe case of sepsis and encephalitis — a form of brain swelling that causes flu-like symptoms, headaches, and confusion. Madilyn’s doctors weren’t optimistic about her chances of survival. “But I was able to hand over that card,” Tschetter-Siedschlaw says. “The doctors said that without that card, they would have probably tried half of the medications Madilyn is not supposed to have.”

Madilyn stayed at the hospital for a month and, at one point, was on 17 medications. Still, things could have been much worse for her, doctors told Tschetter-Siedschlaw, if they hadn’t known quickly which drugs to avoid. “What may have saved her was that the doctors didn’t waste any time experimenting with other [drugs],” Tschetter-Siedschlaw says.

Yet, in many cases, doctors prescribe medications without such knowledge. The Institute of Medicine estimates that the U.S. healthcare system spends $3.5 billion annually treating patients for drug-related adverse reactions. The Centers for Disease Control and Prevention says there are 700,000 emergency room visits and 120,000 hospitalizations each year resulting from ill effects from medications, but many of these events can be prevented. One of the ways in which some healthcare providers are trying to reduce the rate of drug-related adverse events is by testing patients for CYP450 markers, particularly patients who have complex health issues and who are on multiple therapies.

David Durham, a neuropsychiatrist in Albuquerque, New Mexico, learned early in his career that genetic testing can help guide treatment decisions for patients. He uses CYP450 testing most readily for his elderly patients. “They are on so many medicines — one could argue even too many medicines — and they have the highest rate of complications from drug-drug and drug-gene interactions,” says Durham, who, in addition to being a practicing psychiatrist, teaches the subject at the University of New Mexico and sits on Genelex’s scientific advisory board.

Although more and more doctors like Durham are learning about the impact of CYP450 gene variations on drug response, testing for these polymorphisms isn’t standard practice in the medical community. In a nationwide survey published in 2012 of more than 10,000 physicians, 98 percent agreed that genetic variation influences how people respond to drugs, but only 10 percent felt “adequately informed” about pharmacogenetic testing, and only 13 percent had ordered a test in the last six months. Moreover, less than 30 percent of surveyed physicians had received any education about the influence of genetics on drug response or about available tests.

Doctors at large cancer centers and academic institutions, such as the University of South Florida’s Moffitt Cancer Center, are more familiar with CYP450 genetic testing than private practitioners are, and they are implementing it in situations where they want to lower patients’ risk of adverse events, as well as the cost of treating them. Moffitt performs CYP450 testing to better manage invasive fungal infections in leukemia patients, an adverse event that can be fatal and can cost as much as $29,000 to treat. The cancer center sees 700 new leukemia patients each year. Approximately 10 percent of leukemia patients are at risk for fungal infections after receiving harsh chemotherapies that weaken their immune systems. “Suddenly, you have a scenario where a little bit of fungus can kill the patient,” says Howard McLeod, medical director at the DeBartolo Family Personalized Medicine Institute at Moffitt.

Doctors at Moffitt manage this risk by prophylactically treating leukemia patients with an anti-fungal drug called Vfend (voriconazole). However, some patients carry a particular CYP2C19 variation that revs up their ability to metabolize the drug to the point where they get none of its anti-fungal effects, which means they remain at risk for infections. If doctors know early on that a leukemia patient is an ultra-rapid metabolizer of this drug, they can start that patient at a higher than normal dose. “We did economic analysis and basically could not find a scenario where preventing one case of fungal infection [with genetic testing] would not be cost-effective,” McLeod says.

Moffitt is also working to integrate a genetic test that doctors can administer to patients before they go into surgery in order to have a better sense of how they will respond to drugs they receive during and after the operation. For example, to ensure that patients don’t vomit while on anesthesia, doctors give them a type of drug called an anti-emetic. “Anesthesiologists are terrified that someone under anesthesia is going to vomit, they’re going to aspirate, get aspiration pneumonia” — when vomit or saliva gets into the lungs or airways — “and they’re going to die,” McLeod says. Aspiration pneumonia during surgery is rare, occurring in 1 out of 10,000 patients, but it’s concerning enough that doctors give patients anti-nausea drugs if they’re going under anesthesia, usually Zofran (ondansetron).

However, 2 to 5 percent of the population who carry an extra copy of the CYP2D6 gene chew up Zofran before it has a chance to do its job, putting them at risk for vomiting under anesthesia and even aspiration pneumonia. Given the rarity of this marker in the population, oncologists might not think to test every surgical cancer patient to make sure he or she is not an ultra-rapid CYP2D6 metabolizer, but anesthesiologists at Moffitt aren’t willing to take that risk, however small. “A 2 percent risk of treatment failure is much higher than they are willing to tolerate in this particular context,” McLeod says. “It was a real eye opener, as we tolerate between a 20 percent and 40 percent failure rate in the use of anti-emetics for the prevention of chemotherapy-induced nausea and vomiting.”

Outside of large cancer centers like Moffitt and academic institutions, CYP450 testing is not commonly performed at community practices, where the majority of people in the U.S. receive care. When Tschetter-Siedschlaw gave doctors at the Blank Children’s Hospital Madilyn’s genetic testing card, that was the first time they had seen CYP450 information on a patient.

Uptake of CYP450 testing in mainstream care is happening, test developers say, but slowly. Jodie Cadieux, Genelex’s director of marketing and product management, says primary care doctors and those who see geriatric patients are the physicians most often ordering tests from Genelex. But specialists in the areas of pain management and psychiatric conditions, where diagnosis is subjective and treatments are variable, have also been early adopters of CYP450 genotyping. Assurex Health is another company that sells tests that gauge CYP450 and other markers that predict how well patients will respond to certain depression, ADHD, and pain drugs. The firm, which says it has tested 75,000 patients to date, recently inked a deal with a network of employers in the Midwest to make its diagnostics available to 90,000 covered lives.

After her daughter’s experience, Tschetter-Siedschlaw often finds herself telling families with seriously ill children about how genetics can influence which drugs their child responds to. Working at a pediatric health program providing support to families, however, she sees that people have a lot of misconceptions about such testing, particularly about cost and insurance coverage. It costs about $100 to analyze each enzyme using Genelex’s service, according to Durham, who doesn’t assess CYP450 markers for all his patients. He only tests those he feels would benefit from it after reviewing their medical history. Most insurers will cover CYP450 testing only after the doctor has shown it was medically necessary for the patient, and coverage policies for specific tests differ depending on the region of the country. Madilyn’s test, for example, was covered by insurance, but in another state, according to local coverage policies, CYP450 testing might fall in the investigational and not medically necessary category. Insurance companies generally provide specific guidelines on coverage for such testing, so patients should be able to contact their individual providers for more detailed information.

The difficult insurance environment is likely giving some doctors pause in performing CYP450 testing. In other cases, the decision whether or not to test patients for these markers might be purely philosophical, Cadieux says. In her experience at Genelex, primary care doctors and specialists focused on treating the whole patient, as opposed to a particular disease or organ, are more receptive to using CYP450 testing. “But I don’t think this [adoption challenge] is unique to personalized medicine,” she says. “I think it’s true of all new procedures and treatment methods in the medical industry.”