In 510 b.c., the Greek philosopher and mathematician Pythagoras recommended that his followers “be far from the consumption of fava beans” (Arch Hellenic Med 2011;11:258-263). The legume-based prohibition has been attributed to the potentially fatal illness that some individuals experience after consuming fava beans, known as favism. This hemolytic anemia reaction stems from a deficiency in the enzyme glucose-6-phosphate dehydrogenase, which in turn is linked to mutations in the G6PD gene (Nutrients 2023;15[2]:343).
Unbeknownst to Pythagoras, favism is one example of how a person’s genetic makeup shapes their response to chemicals—the foundation of the field today known as pharmacogenomics (PGx) (Heart Fail Clin 2010;6[1]:1-10). As a subset of precision medicine, PGx uses genetic testing to determine which drug and dose are most likely to be effective for a given patient. Implementing PGx into routine clinical care has the potential to mitigate the “trial-and-error” element of drug selection, prevent adverse drug reactions (ADRs) and cut costs associated with these events, speakers said during the ASHP 2023 Summer Meetings & Exhibition, in Baltimore, and the APhA2023 Annual Meeting & Exhibition, in Phoenix.
“This is an area where we know we could impact patient lives and their healthcare quality and safety, and yet [PGx] is not routinely done as part of clinical care worldwide,” said Marylyn D. Ritchie, PhD, MS, BS, the director of the Institute for Biomedical Informatics at the University of Pennsylvania Perelman School of Medicine, in Philadelphia. PGx faces formidable implementation challenges, including the need for evidence of improved patient outcomes and cost-effectiveness, patient and provider education, and the vast pool of patients carrying relevant gene variants.
“We’ve really been pushing at Penn that pharmacy needs to own the implementation of this, and it’s the pharmacists who we need to train to be the experts,” Dr. Ritchie told ASHP meeting attendees.
The importance of pharmacists championing PGx was also stressed by Shawn Dalton, PharmD, BCPS, BCACP, BCPP, PN1-NC, VHA-CM, the telepharmacogenomics national program manager at the Veterans Health Administration, in an APhA session. “Pharmacists will be leading the charge on this across the system,” he predicted.
This series will explore the opportunities and roadblocks for PGx in pharmacy practice. This first installment provides background on PGx and how pharmacists can broaden its use in the clinic.
Potential Applications of PGx
Pythagoras may have described the first example of a pharmacogenetic trait (Drug Discov Today 2011;16[19-20]:852-861), but it was not until 1959 that geneticist Friedrich Vogel coined the term “pharmacogenetics” to describe how genetics affect drug response (Pharmacopsychiatry 2020;53[4]:155-161). Although the terms are often used interchangeably, Dr. Ritchie said, pharmacogenetics is the study of a single or a few gene–drug interactions, whereas pharmacogenomics involves the study of many genes or the entire genome. “They largely mean the same thing; we’re trying to understand what in our genome is impacting how we respond to medications,” she said.
The first pharmacogenetics test to secure FDA approval, in 2004, was Roche’s Amplichip CYP450, which analyzes genes relevant to the metabolism of various psychiatric, immunosuppressive and anticancer drugs (Mol Diagn 2005;9[3]:119-127). Since then, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published 26 peer-reviewed guidelines to help clinicians understand how to use genetic test results to optimize prescribing (see box). “These [guidelines] tell you how to dose, not whether to do the testing; they [assume] that health systems are going to start having preemptive genotyping available,” Dr. Ritchie said.
The genes described in the CPIC guidelines are relevant to a wide array of drugs, including chemotherapy, psychiatric medications, anticoagulants, and medications for pain, hepatitis, nausea, kidney disease, seizures, gout and epilepsy. “Part of the challenge is how many medications this impacts,” Dr. Ritchie said, adding that researchers will continue to discover more gene–drug relationships.
3 Case Studies Show Power Of Genetic Testing
During a presentation on pharmacogenomics (PGx) at the ASHP 2023 Summer Meetings & Exhibition, in Baltimore, Marylyn D. Ritchie, PhD, MS, BS, described three case studies that vividly illustrate the importance of using genetic testing to guide prescribing.
One case occurred while Dr. Ritchie—now the director of the Institute for Biomedical Informatics at the University of Pennsylvania Perelman School of Medicine, in Philadelphia—was a faculty member at Vanderbilt Health. In January 2010, a 57-year-old woman was admitted with angina, received a stent and began taking clopidogrel. “This is the standard, typical treatment,” Dr. Ritchie said. Yet the woman experienced an in-stent thrombosis—a crisis that would repeat seven times that year. By December, the health system had implemented preemptive genetic testing, and the patient was genotyped. It turned out that she carried an allele that prevented her body from metabolizing clopidogrel. “This poor woman was taking this medication every day and she could have just as easily just thrown it over her shoulder because her body was not metabolizing it; it was not doing anything for her,” Dr. Ritchie said. The patient was switched to prasugrel and her condition stabilized.
Another harrowing case concerned a 55-year-old woman who underwent multiple surgeries for a musculoskeletal disorder but had no history of bleeding or clotting disorders. Following shoulder surgery, the patient developed significant hematomas and upper-extremity deep vein thrombosis, and was referred to the emergency department (ED) at Stanford Health Care. “This patient was pretty savvy about pharmacogenomics,” Dr. Ritchie said. The patient told her doctor that she had undergone genetic testing and requested that her warfarin be dosed according to the pharmacogenetic algorithm developed by the International Warfarin Pharmacogenetics Consortium (N Engl J Med 2009;360[8]:753-764). “Her doctor said, ‘No, I’m not doing that. I’m going to dose you the way I dose everyone,’” Dr. Ritchie recounted. “She ended up in the hospital, in and out of ICU for 36 days.” Eventually, the patient received the appropriate dose of warfarin. This patient was none other than Teri Klein, PhD, a professor of biomedical data science at Stanford University and a member of the International Warfarin Pharmacogenetics Consortium.
The third patient whom Dr. Ritchie described was Angela Anderson, a 22-year-old woman of European and Asian American ancestry who died four days after presenting with an eye infection, fever and rash. Doctors determined the cause to be Lyell’s syndrome, or toxic epidermal necrolysis, a skin condition that is usually an adverse drug reaction (in this case, probably to ibuprofen). Postmortem genetic testing revealed that Ms. Anderson carried a genetic variant likely responsible for the reaction, as did one of her parents. Although this variant is most common in East Asian populations, Ms. Anderson inherited it from her European-ancestry parent. This case demonstrates that for PGx to improve patient safety, it must be applied broadly, even if actionable alleles vary in prevalence among different demographics. “We can’t say, ‘We should genotype this population or that population,’” Dr. Ritchie concluded. “If we’re going to implement it, we should be genotyping everyone.”
Most people carry at least one actionable pharmacogenetic variant. In several recent studies, an estimated 95% to 99% of participants had alleles with relevance to PGx (Clin Pharmacol Ther 2016;100[2]:160-169; JAMA Netw Open 2019;2[6]:e195345). In an analysis of 3.3 million Penn Medicine patients, Dr. Ritchie and her colleagues determined that 98.9% of participants carried one or more PGx genes for which treatment modification would be recommended, and 14.2% of participants were prescribed medications that could be affected by their genotype (J Transl Med 2022;20[1]:550). This group included 856 participants who received the antiplatelet medication clopidogrel and carried CYP2C19 reduced function alleles, which placed them at increased risk for major adverse cardiovascular events.
One goal of PGx is to prevent ADRs, which cause an estimated 1.3 million emergency department visits every year, according to the CDC (bit.ly/49ZPa5k). To this end, the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions randomized controlled trial assigned patients from seven European countries to receive genotype-guided drug treatment using a 12-gene PGx panel or standard care (ClinicialTrials.gov Identifier: NCT03093818). Of participants with an actionable test result (n=1,558), patients in the intervention group had a 30% relative risk reduction for clinically relevant ADRs compared with the control group (Lancet 2023;401[10374]:347-356).
Meanwhile, a meta-analysis found that PGx testing increased medication changes: 54.7% of patients in PGx-tested groups had a medication change, compared with 41.5% in the treatment-as-usual group, while reducing hospitalizations (43% reduction). Although limited by the small number of studies and diversity of settings, the authors wrote, “the results show proof of concept for the use of PGx in prescribing that produces patient benefit” (Front Genet 2021 Jul 30. https://doi.org/10.3389/fgene.2021.698148).
Even if a drug does not cause dangerous side effects, it may simply not be effective for a given patient. “My background is in psychiatry, substance use disorders and pain management,” Dr. Dalton noted. “When you have 20% to 30% success rates and really high failure rates, anything that moves that needle even a little bit is at least worth consideration.”
PGx could move that needle by identifying genetic traits that affect how a person’s body will absorb, distribute, metabolize and excrete drugs. Ideally, Dr. Ritchie said, a patient’s prescription would be based on their genetic makeup as well as clinical and demographic factors such as age, diet and preexisting medications. “We want to give people the right dose and the right treatment at the right time, not, ‘Let’s try this one and if it doesn’t work, come back in six weeks, then we’ll give you a different one,’” she said.
In addition to preventing ADRs and streamlining drug selection for a given patient, PGx could decrease healthcare costs. “As we think more and more about value-based care—which is a direction that this country is really moving in—if we have the genetic information on all of our patients such that we gave them the right medication, the potential to … save money and then increase value and make our healthcare quality better for our patients is really high,” Dr. Ritchie said. However, she added an important caveat: It takes time to evaluate the extent to which PGx improves patient outcomes. “We would need to implement this and adopt it systemwide and watch it for years to truly know whether it’s been cost-effective,” she said.
Dr. Ritchie also sees opportunities for PGx to make clinical trials more efficient. “Thousands of drugs never make it through clinical trials because they have adverse drug reactions in some subgroups of patients, and as it turns out, a lot of those are due to underlying genetics,” Dr. Ritchie said. With genotype-guided trials, researchers could target subpopulations most likely to respond well to the investigational drug. “Even if in the end we don’t get the blockbuster drug that treats everyone, we [are more likely to] get drugs that make it through trials,” she said.
Many healthcare systems and academic medical centers have incorporated PGx into clinical care, Dr. Ritchie noted, including Vanderbilt Health, University of Florida Health, St. Jude Children’s Research Hospital, Mayo Clinic, UPMC (formerly the University of Pittsburgh Medical Center) and Penn Medicine. However, she acknowledged, scaling up PGx is not an easy proposition.
One hurdle is the logistical difficulty of adopting PGx testing systemwide. “The reality that [PGx] impacts potentially so many of our patients is like a blessing and a curse,” she said. “Many of us carry pharmacoalleles that, if we never get prescribed the medication, won’t ever be important for us. … So, it’s having the information on everyone, for the small percentage who will go on that medication.” As sequencing becomes less expensive, she said, this will become a more feasible undertaking.
Pharmacogenomics Resources
To learn more about PGx, peruse the Pharmacogenomics Knowledge Base (www.pharmgkb.org), suggested Marylyn D. Ritchie, PhD, MS, BS, the director of the Institute for Biomedical Informatics at the University of Pennsylvania Perelman School of Medicine, in Philadelphia. The National Institutes of Health–funded online database, which is housed at Stanford University, provides detailed information about how genetic variations affect drug responses. Visitors can search for specific drugs, genes, pathways of interest and clinical guidelines. “This is an extremely comprehensive online resource for pharmacogenomics,” Dr. Ritchie said.
Convincing payors about the value of PGx testing is another concern. “With insurance, this is one of the conversations: ‘Does it matter for the patient right now while they’re under my insurance?’ Sometimes it’s not going to matter for years,” Dr. Ritchie said. “And [PGx] covers so many therapeutic areas; maybe the test doesn’t matter in the clinic you’re in today, [but] it matters when you’re in a different clinic four years from now and you’re prescribed another drug.”
The extent to which PGx is cost-effective will depend on a variety of factors, Dr. Dalton said, including the patient population in question, cost and availability of testing, risks related to the medication given, and severity of ADRs avoided. “If all we’re preventing is mild nausea, maybe PGx wouldn’t be worth it. For preventing a hospital admission or a death? Very different conversation.”
In one review of PGx studies, researchers found that if genetic information were freely available (i.e., discounting the cost of the genetic test itself), 75% of economic evaluations would support PGx-guided treatment, of which 25% would be cost-effective and 50% cost saving (Pharmacogenomics J 2017;17[5]:395-402). Based on current levels of evidence, he said, PGx panels are one-time tests with potential lifelong benefits, although future testing may be appropriate with advancements in science.
Although coverage for PGx is inconsistent across all insurers, UnitedHealthcare and Blue Cross Blue Shield already cover PGx testing for some indications, Dr. Dalton noted. “If you have those healthcare plans, you can go get a 15-gene panel today and [if approved], the maximum out-of-pocket cost is generally going to be around $300,” he said.
Dr. Dalton listed several additional limitations to PGx, including variability in alleles tested by different companies, disparities in the representation of different ethnic groups in PGx panels or clinical studies, and the inability of PGx tests to evaluate drug interactions or account for how epigenetics influences drug metabolism.
Patient and provider education is also an important consideration for PGx implementation. “We basically need to teach every specialty about pharmacogenomics, and this is something that today just is not prevalent in medical school education,” Dr. Ritchie said. “How do we now teach all of them?”
Health systems ignore this task at their peril. “We are starting to see lawsuits in this space for health care systems not doing testing,” Dr. Ritchie warned. In one noteworthy case, Oregon Health & Science University (OHSU) paid $1 million to settle a suit from a woman whose husband died after receiving capecitabine for bile duct cancer. The patient experienced an ADR due to dihydropyrimidine dehydrogenase deficiency, a situation that could have been avoided had the patient been tested for this genetic condition, his widow contended. As part of the settlement, OHSU agreed that its oncologists would be required to educate patients about dihydropyrimidine dehydrogenase deficiency before initiating capecitabine, and the university would include education about the condition in its oncology fellowship program (bit.ly/3N8coMO). “This is an example where while people have been saying, ‘Well, it’s not in the cancer guidelines; we don’t have to do it,’ that’s not standing up in the legal system,” Dr. Ritchie said.
For PGx expansion to succeed, health systems need to add genetic testing protocols to clinical decision support and other key software systems, including electronic health records (EHRs). “If we don’t build this in an EHR so that it lives on beyond that one provider interaction with the patient, this will absolutely fail,” Dr. Ritchie said.
At Penn Medicine, she and her colleagues launched the PennChart Genomics Initiative to integrate genomic data into the EHR. They developed a precision medicine tab using Epic’s Genomics Indicators module to house test results, annotate them for PGx variants, and alert providers when necessary (Genet Med 2021;23[4]:603-605). “When you prescribe a drug, if they have a [relevant] variant, then it will tell you this patient shouldn’t go on the drug,” Dr. Ritchie said.
Penn Medicine also built a Genetic Profile into its patient portal where patients can view their results with annotated educational information.
The Pharmacist’s Role
Dr. Ritchie hopes to see PGx testing become routine within the next decade or two. “We have a lot of challenges to face, but I think they are manageable,” she said. “We need partnerships between the genetics people who can do the lab stuff and pharmacists who actually understand how drugs are metabolized, and then to teach all of our other providers how to [apply the results of pharmacogenomics testing].”
In a review of 12 completed and three ongoing PGx analyses in adults with multimorbidity or polypharmacy, several studies reported reductions in hospitalizations and ED visits following genetic testing and prescribing optimization (40% and 70%, respectively, in one study, and 52% and 42% in another), and several reported estimated improvements in healthcare costs that ranged from $788 per patient over 16 weeks to $4,382 per patient over eight weeks (Pharmacogenomics J 2022;22[2]:89-99).
Despite its small sample size, the review underscored the importance of pharmacists in PGx efforts. The authors noted that most of the studies involved pharmacist-led medication management. “With their training, frequent patient contact and role in medicines optimization as well as medication surveillance, pharmacists may be leading candidates to ... [incorporate] pharmacogenetics into medicines optimization,” the team wrote.
The Department of Veterans Affairs has genotyped more than 20,000 veterans, Dr. Dalton said. He views PGx as one piece of a larger puzzle that pharmacists already have substantial experience with. “Things like diet, our lifestyle, our stress levels, how well we sleep, our comorbidities—that all impacts how we tolerate medication as well,” he said. “I encourage everybody to see [PGx] as an additional data point that we use in considering how to treat our veterans, not as the only tool.”
Dr. Dalton proposed several steps to address PGx implementation challenges:
- educate facility leadership and clinical staff, including physicians, laboratory personnel and pharmacists, about PGx;
- write position papers or business plans to communicate the benefits of early adoption of PGx;
- develop a multidisciplinary PGx committee;
- select a pharmacist champion for PGx to bridge disciplines; and
- develop policies, software and infrastructure to support PGx use.
Pharmacists at all organizational levels will participate in these efforts, noted Anthony P. Morreale, PharmD, MBA, BCPS, the associate chief consultant for Clinical Pharmacy, Policy and Pay at the VA. Key personnel in those efforts include directors of pharmacy, who can help guide PGx implementation into their healthcare system, to advanced practice pharmacists using PGx to inform prescribing decisions, Dr. Morreale said at the APhA meeting. He described several ways that pharmacists can contribute to PGx efforts, including:
- recommend or schedule PGx testing to aid drug and dosage selection;
- educate patients about PGx;
- combine PGx test results with traditional pharmacodynamic and pharmacokinetic variables, drug interactions, and potential ADRs; and
- communicate PGx-informed drug therapy recommendations to healthcare teams and patients.
To assess workforce preparedness for PGx, Dr. Morreale and his colleagues at the VA surveyed 674 pharmacists, most of whom held advanced clinical roles. Only 29% of respondents reported having any training in PGx. “That was a bit surprising,” he said. In addition, when queried about their comfort level in performing various PGx-related patient care services, “nearly all had some level of discomfort with applying pharmacogenomics to direct patient care.”
However, most respondents indicated that they were receptive to PGx education programming, with an average interest level of 78 on a 0-100 scale. “The bad news was they don’t really know yet how to implement or apply pharmacogenomics systemwide. The good news is they all want to be trained,” Dr. Morreale said. The survey results suggested that “if we can scale up an appropriate training course for pharmacists and pharmacogenomics, then we can change our landscape.”
The VA is developing programs that aim to incorporate real-world training experience, include pharmacy residents in PGx training opportunities and apply PGx training to existing VA pharmacy practice models. One such program is the Expanding Clinical Pharmacist Practitioners in Pharmacogenomics (EXCLAIM) project, which provides facility implementation support and PGx training, and aims to hire 120 pharmacists across the VA.
“There’s this recognition that without the pharmacists, we’re not going to be able to scale up pharmacogenomics,” Dr. Morreale said. “We do know that our physician and pharmacist workforce are not sufficiently trained to deal with the rapid evolution of the science. However, there is evidence that training our 11,000 pharmacists is going to yield amazing results in terms of integrating pharmacogenomics into what pharmacists do every day.”
The sources reported no relevant financial disclosures.
This article is from the January 2024 print issue.