Getting Pharmacogenomics Into the Clinic | JAMA | JAMA Network | September 21, 2016. doi:10.1001/jama.2016.12103
What if there were a way to know if a depressed patient would respond to an antidepressant—before it was prescribed? Or to predict a bleeding event from an antiplatelet therapy?
In recent years, advances in genetic testing have made such drug-response predictions possible for patients with certain gene variants.
But physician adoption is moving slowly, say experts in the growing field of pharmacogenomics.
“While we’ve made tremendous rapid advances in terms of basic science and technological advances, and [while] clinical outcomes [are] there for some gene-drug pairs, clinical implementation unfortunately has been lagging behind,” said Edith A. Nutescu, PharmD, MS CTS,
In the results of a nationwide survey by the American Medical Association released in 2012, only 13% of more than 10 000 responding physicians had ordered a pharmacogenomic test in the previous 6 months, although almost all of them—98%—agreed that drug responses may be influenced by genetic variations.
Genotype-guided prescribing—also referred to as pharmacogenetics, or PGx—is expected to become routine as genetic profiling becomes more commonplace.
“[I]t is likely that a time will come in the near future where patients will start to demand the use of such information during care—that they will ask of their physician, ‘Have you considered my genomics?’ before accepting a prescription,” said Peter H. O’Donnell, MD, associate director for clinical implementation at the University of Chicago’s Center for Personalized Therapeutics.
For those of us taking large doses of opioids, this change cannot come soon enough. There is a strong genetic factor in how a person metabolizes opioids, so pharmacogenetic testing is essential for determining how well an individual metabolizes opioids.
- Cytochrome P450 Testing In High-dose Opioid Patients and
- Pharmacogenetics of chronic pain management.
In the meantime, major efforts are under way to prove that pharmacogenomic tests have clinical utility and to make it easier for physicians to choose these tests and interpret and act on the results, translating them into better outcomes for their patients.
HOW DOES PHARMACOGENOMICS WORK?
“Genetic variability affects essentially every single gene in the human genome and sometimes it’s going to affect genes whose proteins are critical for drug response,” said Mary V. Relling, PharmD
Most so-called pharmacogenes encode drug-metabolizing enzymes, and each individual’s genotype for a particular gene can be categorized into 1 of 5 phenotypes that describe the enzyme’s activity—
- ultrarapid metabolizer,
- rapid metabolizer,
- normal metabolizer,
- intermediate metabolizer, and
- poor metabolizer.
Other genes encode the enzymes that are the site of action where drugs exert their effects; patients with variations in these genes may be more sensitive or resistant to certain drugs than normal.
Knowing this information can help clinicians choose the right medication or dose for a patient.
A patient who has a genetic variant associated with slow metabolism of the drug thinner warfarin, for example, might experience major bleeding on a standard dose. In contrast, a patient with a variant associated with fast warfarin metabolism might not get any benefit from the standard dose, putting them at greater risk of a major stroke or thromboembolism.
“Warfarin is consistently among the top 10 medications that leads to hospitalizations due to adverse events,” Nutescu said. “Drugs that are more prone to side effects, complications, hospitalizations, [and] resource use, clearly should be on the radar.”
Pharmacogenomics may also help inject more science into the art of prescribing.
the technology has the potential to transform antidepressant treatment for major depressive disorder, multiple anxiety disorders, and some chronic pain conditions.
BUILDING A CASE
According to a 2015 Nature review article that Relling coauthored, drugs currently known to be affected by “actionable” inherited pharmacogenes represent around 7% of FDA-approved medications and 18% of US outpatient prescriptions.
In addition to antidepressants and blood thinners, these drugs include, antivirals, chemotherapy agents, immunosuppressants, pain relievers, and statins, among others, making the field of pharmacogenomics relevant for precision medicine in a variety of medical specialties.
“It is my view that someday—probably not far in the future—we will look back on the idea of treating all patients who have the same ‘disease’ with the same drug as a simply archaic practice,” O’Donnell said in an email.
It has become obvious to anyone familiar with the literature that genetic differences between individuals make “standard” treatments of all kinds obsolete.
Because standards are created only for the “statistically average” human being (who statistically has one breast and one testicle), setting treatment standards for diverse populations is an unscientific practice.
Unfortunately, the CDC is far, far behind the curve.
This supposedly health-related agency refuses to acknowledge the reality of genetic differences in their ludicrous idea of arbitrary opioid dose limits.
To help advise physicians, the international, nonprofit Clinical Pharmacogenetics Implementation Consortium (CPIC) has written guidelines for gene-drug pairs that the group believes have sufficient evidence from randomized controlled trials and other clinical studies to influence prescribing.
The CPIC has identified more than 300 gene-drug pairs of interest.
Relling, who co-leads CPIC, said that about half of those will have actionable prescribing based on genetics.
So far, the group, which focuses on inherited genomic variations, has released clinical practice guidelines for 13 genes affecting the response to more than 30 drugs.
BARRIERS TO ENTRY
O’Donnell added, “Decision-support—in other words, guidance about how to use genomic information—is needed for prescribers who will be increasingly encountering pharmacogenomic results for their patients, because most clinicians in practice have not been formally trained in genomics.”
To that end, the IGNITE website offers a toolbox of resources for health systems and clinicians, such as example clinical decision support alerts for electronic health record (EHR) systems and test result decision tables.
a CPIC group that recently published standardized pharmacogenomics terms in Genetics and Medicine that can be interpreted exactly the same way across all EHR systems.
Pharmacogenomics leaders say that a lack of reimbursement for genetic tests is another huge challenge that cannot be underestimated.
The Centers for Medicare & Medicaid Services does not cover panel-based testing, which Johnson said is often the most cost-effective and logical approach to pharmacogenetics-guided treatment.
“Even though the cost of genetic tests is coming down all the time, somebody has to bite the bullet and pay for that test, and we just don’t have a health care system that’s geared toward doing that at this point,” Relling said.
We don’t have a health care system that’s geared toward anything but profit.
Johnson believes that clearing up reimbursement issues would be one of the fastest ways to get doctors to embrace pharmacogenomic testing.