Standardizing Practice for Pharmacogenomics Testing

How can a better understanding of genetics make lifesaving medicine safer and more effective?

Children’s Hospital Colorado’s whole-genome sequencing lab provides endless opportunities for more precise diagnosis and treatment of genetic diseases. One area where the lab’s capabilities are already having a significant impact is in pharmacogenomics, a field of study that seeks to understand how a person’s genetic makeup influences their response to medications.

“There are specific genes that have implications on how we respond to a drug, whether or not it’s effective and whether or not we’re able to break it down,” explains Elizabeth Fenstermacher, MD, who serves as co-chair of the Genomics Application Governance Committee (AGC) at Children’s Colorado. Gene variants can influence drug metabolism across a spectrum: Some patients may be intermediate metabolizers, which means they tolerate lower doses of certain drugs, while poor metabolizers may not be able to take them at all.

For example, some people are born with variants in the genes thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15), which influence how they metabolize immunomodulator drugs called thiopurines. These medications, such as azathioprine, are used to tamp down the immune system when a patient has a blood-borne cancer or rheumatologic disease. Azathioprine is also an important medication for preventing organ rejection after a donor transplant.

About 1 in 10 people has a gene variation that causes a partial reduction of TPMT activity and about 1 in 300 people has a severe reduction of activity. “If you have variants in those particular genes, you may not break down those medications as well,” Dr. Fenstermacher says. “It can be really dangerous — and even fatal — if you were to get standard dosing of those medications.”

That’s where pharmacogenomics comes in. Testing patients for these gene variants before prescribing thiopurines can prevent potentially catastrophic outcomes and ensure the drugs work as intended.

Laboratory practice guidelines

The pharmacogenomics team at Children’s Colorado and the University of Colorado School of Medicine, which includes pharmacy leaders, laboratory analysts, geneticists and technology experts, began its initiative in November 2024 by incorporating TPMT and NUDT15 variant information into Epic, the hospital’s electronic health record system.

“We’re starting with these two high-priority genes, but now that we’ve built the framework, we plan to phase in additional genes as rapidly as we can,” Dr. Fenstermacher says. Next, the team plans to use scientific literature and guidance from subject matter experts to determine which additional genetic information to include in Epic. Variations with the strongest potential for patient harm will take priority.

This rapid implementation is made possible by Epic’s built-in genomics module, which makes it easy for providers to understand their patients’ genomic indicators. These are not diseases or diagnoses, explains Children’s Colorado geneticist Austin Larson, MD, but rather, differences that could determine how patients respond to medications.

“We have the ability to attach genomic indicators to patients’ health records, and then the genomic indicators trigger decision support for clinicians dynamically,” Dr. Larson says.

This information is all strategically located in the same area where providers would find allergy information, so if they do prescribe azathioprine to someone who’s considered a poor metabolizer, Epic will immediately prompt them with a warning — and instructions on what to do next. These directives involve detailed guidance from Children’s Colorado’s OurPractice Advisory, or OPA, a tool within Epic that allows hospitals to share organization-wide reminders and clinical action items that can support provider workflows. They can also access information on how to proceed in the presence of comorbidities (if a patient also has Down syndrome, for example), and call for extra support if needed.

“You can get a one-click pharmacy consult if you need to talk to a pharmacist about the specific clinical circumstances, learn how much to reduce the dose or determine if a different medication is needed,” Dr. Larson says. “Instead of overwhelming providers with a list of 30 things their patient needs, the goal is to provide the genetic information to the right person at the right time with specific actions that they can take.”

The Genomics AGC will ensure that providers across the institution are updated and informed of this Epic change, and they will all be invited to learning sessions where they can better understand the drugs they commonly prescribe, and which genetic variants might put their patients at risk.

Looking ahead, the team plans to include pharmacogenomic guidance for all kinds of inherited diseases, from neurofibromatosis type 1 to sickle cell disease. “We’re able to push out education across the institution using these OPAs as a way that we make sure everybody is prescribing with the best practices following the most recent clinical guidelines developed with international consensus,” Dr. Fenstermacher says. “I think it’s really an incredible tool.”

Standardizing pharmacogenomic information in patient charts isn’t just important for current treatments, but also for nuanced medical needs that may arise in the future. “We can generate new information from the data that we already have and turn on a genomic indicator for all our patients without anyone getting a new test,” Dr. Larson says. “We can improve the quality of the data and improve the quality of the decision support, iteratively, on an ongoing basis.”

In other words, when used for whole genome sequencing, a single buccal swab at age 9 can continue informing a person’s treatment throughout their lifetime.

Pediatric pharmacogenomics research

At the national level, Children’s Colorado pharmacogenomics clinical pharmacist Christine Formea, PharmD, is joining broader conversations through participation in the Standardizing Laboratory Practices in Pharmacogenomics (STRIPE) forum, which is part of the American Society of Pharmacovigilance.

“This collaborative community brings stakeholders from across the country together to start thinking about creating standards,” Dr. Formea says. “How do we focus resources toward standardization, having common language and understandings?”

At the most recent STRIPE national meeting, Dr. Formea helped moderate panel discussions and was honored with the organization’s Double Helix Award, which recognizes leadership in advancing the field of pharmacogenomics.

“My hope is we are able to remove barriers to access and make genetic testing available to all of our patients at a low cost,” Dr. Formea says. “There’s tremendous opportunity for this program to grow even larger as we incorporate more genes and drugs, and to impact more patients in meaningful ways by providing medical safety and improving patient care.”