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Utilizing Pharmacogenomic Testing Can Improve Medication Safety and Prevent Harm

Problem: Genetic variations have been used to identify the potential for disease, but the impact of genetic variations on an individual’s response to medications, referred to as pharmacogenomics (PGx), is not yet as widely used. In our 2021 newsletter article, Screening for dihydropyrimidine dehydrogenase (DPD) deficiency in fluorouracil patients: Why not?, we shared how saddened we were to learn about a patient’s death that may have been prevented if DPD deficiency testing had been completed prior to starting fluorouracil. Having this information beforehand allows prescribers to preemptively reduce the dose of the patient’s medication and mitigate potential toxicities, or avoid the therapy if the patient has DPD deficiency. Since then, we have received additional reports of patient deaths from the lack of screening for DPD activity prior to initiation of fluoropyrimidines (i.e., fluorouracil, capecitabine). In reviewing the literature surrounding the hesitancy to adopt universal screening, the risk of patient harm and potential fatality seems clear, and the hurdles to implement widespread testing seem to be manageable. Our position in support of DPD testing remains the same. 

Furthermore, in 2022, the US Food and Drug Administration (FDA) approved updated prescribing information for XELODA (capecitabine) to warn about serious, including fatal, adverse drug reactions (ADRs) from DPD deficiency, and recommends that prescribers discuss with patients whether they should be evaluated for genetic variants associated with this risk. Just recently, in March 2024, FDA approved similar labeling changes for fluorouracil injection products. In 2022, one organization, Dana Farber, implemented a reminder-based PGx testing program for patients prior to receiving fluoropyrimidines, achieving a testing rate of 90%. During the first 10 months, the program screened 1,043 patients and was able to identify 43 at-risk patients who were evaluated for preemptive dose reductions.1 

Since our article was published, the integration of pharmacogenetic testing into clinical practice for several medications has become more widespread, aiming to prevent ADRs, optimize dosing, and enhance patient safety.2 However, not all healthcare practitioners and organizations are aware of the vast array of medications that have testing recommendations, or the potential for patient harm if it is not done. While testing is mostly covered by insurance, this varies from state to state, as does cost-effectiveness, which varies by organization depending on volume and laboratory test availability. Other challenges include test result turnaround time (e.g., 3 days for in-house versus 5 to 10 days if using an external laboratory), laboratory variability in the comprehensiveness of genotype testing, difficulty interpreting test results, and a lack of knowledge regarding adjustment of drug doses based on the results. Consequently, practitioners may lack expertise on how to implement a PGx program to prevent medication-related harm in their organization. 

For this reason, we sought insights and best practices for incorporating PGx into clinical care from experts in the field. Practitioners at South Florida’s Nicklaus Children's Hospital (previously known as Miami Children’s Hospital) have pioneered personalized medicine for pediatric care, offering insights and best practices for integrating PGx testing to enhance medication efficacy and reduce ADRs.3 Their innovative PGx program is at the forefront of precision medicine and is described below.

Pharmacogenomic Program Overview

The PGx program at Nicklaus Children's Hospital provides personalized treatment plans for various conditions, including behavioral health issues, oncology, pain management, and infectious diseases. The program is founded on three pillars: an extensive PGx test panel, available in-house; advanced clinical decision support (CDS) systems integrated with electronic health records (EHRs); and a team of PGx experts committed to supporting practitioners and educating patients about PGx test results.

PGx testing can be both reactive and preemptive. Reactive testing occurs when a medication has already been prescribed and involves genes known to influence the drug's efficacy. In contrast, preemptive testing is conducted before any medication is needed, allowing for the anticipation of potential genetic interactions with future treatments. The program at Nicklaus Children's Hospital focuses on preemptive PGx care, and results are stored within the EHR for future reference. 

Current Guidelines 

The Clinical Pharmacogenetics Implementation Consortium (CPIC), supported by the National Institutes of Health (NIH), is an international consortium whose interest is facilitating the use of PGx tests for patient care. The group has been instrumental in providing recommendations for dose adjustments, identifying medication hypersensitivity risks, and has developed more than 26 guidelines for 25 genes relevant to 90 drugs,4 including for fluoropyrimidines based on dihydropyrimidine dehydrogenase genotype. In addition, the FDA-approved labels for these adult and pediatric medications now include PGx-based dosing recommendations and hypersensitivity risk assessments, highlighting the critical role of PGx in enhancing medication safety.5 

Impact of Testing 

At Nicklaus Children's Hospital, PGx test results are used to assess the activity of enzymes, which play a vital role in the metabolism of many medications. The expansive PGx testing panel includes screening for gene variants to preemptively identify patients at risk of DPD deficiency. This proactive approach enables tailored dosage adjustments, significantly mitigating the risk of severe drug-induced toxicity. 

When it comes to medications used in behavioral health, genetic variation in drug metabolizing enzymes cytochrome P450 (CYPs) CYP2D6, CYP2C19, and CYP2B6 can affect how several antidepressants are metabolized, potentially influencing their dosing, effectiveness, and side effect profile. Practitioners use this information to determine appropriate dosing and drug selection.6 To cite another example, the metabolism of most proton pump inhibitors is influenced by the CYP2C19 enzyme, with variations in the CYP2C19 genotype affecting medication exposure, effectiveness, and side effects. Practitioners can tailor proton pump inhibitor therapy using the patient's PGx profile.7

In more critical cases, PGx results related to CYP2C9 and/or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes can predict high sensitivity to warfarin, where standard doses may increase bleeding risks.8 Additionally, alterations in the thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes can lead to the accumulation of harmful metabolites, increasing toxicity risks with standard thiopurine medication doses. Preemptive genetic testing for TPMT and NUDT15 is a recognized protocol across numerous institutions, guiding thiopurine treatment.9 

These examples highlight the impact of PGx testing implementation on medication safety.

Safe Practice Recommendations: We encourage organizations to evaluate the feasibility of implementing a PGx program and consider the following recommendations: 

Designate a team and gather resources. Review your organization’s position on PGx testing and assess the need for establishing, modifying, and/or expanding services. Review the CPIC guidelines,4 prescribing information, and published literature to identify medications on your organization’s formulary that have associated PGx tests. To better understand what tests and precision therapies are backed by clinical evidence, refer to ECRI’s Genetic Test Assessment membership website.

Evaluate medications with available guidelines. Complete a gap analysis by comparing available PGx guidelines versus your organization’s current testing status to develop and prioritize a list of medications for testing. Incorporate this as part of the review process when new drugs are evaluated for formulary addition. 

Develop organizational guidelines. Guidelines will be needed to identify patients who should be screened with PGx testing based on the established list of medications and/or other patient risk factors. Include resources and guidelines on how to interpret test results. If a genetic variant is detected that requires a medication to be withheld or dose adjusted, include this information in the guidelines. Review and update the guidelines at least annually or sooner based on data (e.g., change in CPIC Guidelines, new test becomes available).

Build guidelines into the EHR. Incorporate the guidelines in the EHR to notify prescribers of the recommended PGx test before ordering medication from the established list (e.g., if a prescriber enters an order for fluorouracil or capecitabine, an alert is generated with the recommended DPD testing prior to initiation).

Choose a laboratory. Meet with laboratory leadership to determine if it is feasible to develop an in-house PGx test or select an external laboratory. Consider turnaround time which may be reduced if in-house testing is used. 

Ensure standardized testing. Follow best practices set by the Association for Molecular Pathology (AMP), including incorporating a fundamental set of genetic variants in the genotyping assay.10 Adhering to these standards ensures the clinical validity of PGx testing, thereby enhancing personalized and effective patient care.

Implement or expand testing. Strive to implement a comprehensive PGx panel covering genetic variants with established clinical guidelines or relevance in targeted medical areas. This comprehensive approach ensures the test results' applicability for an array of different conditions and serves the patient throughout the continuum of care. Develop a means to track patients so that the team will know that their initiative has reliably reached the right patients. 

Determine preemptive testing. When feasible, conduct preemptive PGx testing prior to initiating the applicable medication. 

Leverage CDS. Integrate PGx testing results along with CDS (e.g., alert for contraindication, dose adjustment) into the EHR. This ensures that practitioners have instant access to essential PGx information, significantly enhancing the clinical decision-making process. 

Educate practitioners. Provide practitioners who will be involved with ordering and evaluating PGx test results with a competency assessment to complete during orientation and at least annually thereafter. Educate staff, for example during grand rounds, about your organization’s guidelines and how to interpret test results and adjust the dose, when needed. 

Educate patients. Review PGx test results with patients and educate them about genetic variations that may impact their medication regimen. Provide them with documentation of the test results and encourage them to share this information with practitioners at applicable care settings (e.g., primary care provider, hospital admission, pharmacy) as part of their medication history. 

Conclusion

The growing adoption of PGx testing that follows established guidelines for drug-gene pairs is increasingly recognized as an important method for tailoring medication choices and dosages, enhancing patient safety and treatment efficacy. ADR avoidance is an additional incentive that can support the return on investment. Insights and recommended practices from PGx professionals at Nicklaus Children's Hospital stress the importance of test standardization, compliance with clinical guidelines, and seamless integration into EHRs as key safety components for effectively integrating PGx testing into clinical care. ISMP supports this shift toward a more personalized approach to preventing ADRs and patient harm. We encourage standard-setting organizations to consider including PGx in their recommended treatment guidelines. 

We thank David Mancuso, PharmD, MS, CPh, PRS, Executive Director of Pharmacy and Laboratory Services, and Steven J. Melnick, PhD, MD, FCAP, Chief, Department of Pathology and Clinical Laboratories, at Nicklaus Children's Hospital for sharing a systematic review of their PGx program, as well as helping to write this article. Email ISMP ([email protected]) with questions for Nicklaus Children's Hospital. 

References

  1. Jacobson JO, Rompelman G, Chen A, et al. Design and implementation of an opt-out, end-to-end, preemptive DPYD testing program for patients planned for a systemic fluoropyrimidine. JCO Oncol Pract. Published online April 12, 2024. doi:10.1200/OP.23.00776   

  2. Implementation. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024.

  3. Pharmacogenomics program. Nicklaus Children’s Hospital. Accessed February 12, 2024.

  4. Guidelines. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024.

  5. US Food and Drug Administration (FDA). Table of pharmacogenomic biomarkers in drug labeling. Updated February 2, 2024. Accessed February 12, 2024. 

  6. CPIC guideline for serotonin reuptake inhibitor antidepressants and CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024. 

  7. CPIC guideline for proton pump inhibitors and CYP2C19. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024.

  8. CPIC guideline for pharmacogenetics-guided warfarin dosing. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024.

  9. CPIC guideline for thiopurines and TPMT and NUDT15. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed February 12, 2024.

  10. Association for Molecular Pathology position statement: best practices for clinical pharmacogenomic testing. Association for Molecular Pathology. Published September 4, 2019. Accessed February 12, 2024.

 

Suggested citation:

Institute for Safe Medication Practices (ISMP). Utilizing pharmacogenomic testing can improve medication safety and prevent harm. ISMP Medication Safety Alert! Acute Care. 2024;29(9):1-4.