Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Incidence of statin-associated muscle symptoms in patients taking statins with RYR1 or CACNA1S variants.

Background: Statins are commonly used medications. Variants in SLCO1B1, CYP2C9, and ABCG2 are known predictors of muscle effects when taking statins. More exploratory genes include RYR1 and CACNA1S, which can also be associated with disease conditions. Methods: Patients with pathogenic/likely pathogenic variants in RYR1 or CACNA1S were identified through an elective genomic testing program. Through chart review, patients with a history of statin use were assessed for statin-associated muscle symptoms (SAMS) along with collection of demographics and other known risk factors for SAMS. Results: Of the 23 patients who had a pathogenic or likely pathogenic RYR1 or CACNA1S variant found, 12 had previous statin use; of these, SAMS were identified in four patients. Conclusion: These data contribute to previous literature suggesting patients with RYR1 variants may have an increased SAMS risk. Additional research will be helpful in further investigating this relationship and providing recommendations.

Implementation of CYP2C19 and CYP2D6 genotyping to guide antidepressant use in a large rural health system.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: We describe the implementation and ongoing maintenance of CYP2C19 and CYP2D6 focused pharmacogenetic (PGx) testing to guide antidepressant and antianxiety medication prescriptions in a large rural, nonprofit health system. SUMMARY: Depression and anxiety are common psychiatric conditions. Sanford Health implemented PGx testing for metabolism of cytochrome P450 (CYP) isozymes 2C19 and 2D6 in 2014 to inform prescribing for multiple medications, including antidepressant and antianxiety therapies. As guidelines, genotype to phenotype translation, panel offerings, and other resources are updated, we adapt our approach. We make educational and informational materials available to providers and patients. Pharmacogenomic clinical pharmacists review PGx results with discrete values and provide guidance documentation in the electronic medical record. A robust clinical decision support system is in place to provide interruptive alerts, noninterruptive alerts, and genomic indicators. A referral-based interdisciplinary clinic is also available to provide in-depth education to patients regarding PGx results and implications. Additionally, partnering with our health plan has expanded access to PGx testing for patients with anxiety or depression. CONCLUSION: The implementation and maintenance of Sanford Health's PGx program to guide antidepressant and antianxiety medication use continues to evolve and requires a multipronged approach relying on both human and informatics-based resources.

The expanding role of HLA gene tests for predicting drug side effects.

Adverse drug reactions can be either dose-dependent (Type A) or idiosyncratic (Type B). Type B adverse drug reactions tend to be extremely rare and difficult to predict. They are usually immune-mediated. Examples include severe skin reactions and drug-induced liver injury. For many commonly prescribed drugs (such as antibiotics), the risk of developing an idiosyncratic adverse drug reaction is influenced by variability in the human leukocyte antigen (HLA) genes. Because these HLA-mediated adverse drug reactions can be lethal, there is growing interest in defining which specific drug-gene relationships might benefit from pre-emptive HLA genotyping and automated clinical decision support. This review summarizes the literature for HLA-mediated adverse reactions linked to common drugs.

Evolution of pharmacogenomic services and implementation of a multi-state pharmacogenomics clinic across a large rural healthcare system.

Introduction: Pharmacogenomics (PGx) aims to maximize drug benefits while minimizing risk of toxicity. Although PGx has proven beneficial in many settings, clinical uptake lags. Lack of clinician confidence and limited availability of PGx testing can deter patients from completing PGx testing. A few novel PGx clinic models have been described as a way to incorporate PGx testing into the standard of care. Background: A PGx clinic was implemented to fill an identified gap in provider availability, confidence, and utilization of PGx across our health system. Through a joint pharmacist and Advanced Practice Provider (APP) collaborative clinic, patients received counseling and PGx medication recommendations both before and after PGx testing. The clinic serves patients both in-person and virtually across four states in the upper Midwest. Results: The majority of patients seen in the PGx clinic during the early months were clinician referred (77%, n = 102) with the remainder being self-referred. Patients were, on average, taking two medications with Clinical Pharmacogenetics Implementation Consortium guidelines. Visits were split almost equally between in-person and virtual visits. Conclusion: Herein, we describe the successful implementation of an interdisciplinary PGx clinic to further enhance our PGx program. Throughout the implementation of the PGx clinic we have learned valuable lessons that may be of interest to other implementors. Clinicians were actively engaged in clinic referrals and early adoption of telemedicine was key to the clinic's early successes.

Advancing Pharmacogenomics-Based Care Through Interprofessional Education.

As genomic medicine becomes increasingly complex, pharmacists need to work collaboratively with other healthcare professionals to provide genomics-based care. The core pharmacist competencies in genomics were recently updated and mapped to the entrustable professional activities (EPAs). The new competency that is mapped to the "Interprofessional Team Member" EPA domain emphasizes the role of pharmacists as the pharmacogenomics experts in an interprofessional healthcare team. Interprofessional education (IPE) activities involving student pharmacists and students from other healthcare disciplines are crucial to prepare student pharmacists for a team-based approach to patient-centered care. This commentary discusses the pharmacogenomics-focused IPE activities implemented by 3 programs, the challenges faced, and the lessons learned. It also discusses strategies to develop pharmacogenomics-focused IPE activities based on existing resources. Developing pharmacogenomics-focused IPE activities will help prepare pharmacy graduates with the knowledge, skills, and attitudes to lead collaborative, interprofessional teams in the provision of pharmacogenomics-based care, consistent with the standards described in the genomics competencies for pharmacists.

Patient satisfaction with return of pharmacogenomic results utilizing a patient portal message.

Background: Returning pharmacogenomics (PGx) results to patients is complex and challenging. Patients prefer provider education; however, a gap in provider comfort in PGx results has been documented. Objectives: This study's purpose was to evaluate satisfaction with the return of PGx test results using a patient portal message. Methods: A survey was sent to two cohorts with PGx results, one that received a PGx result message and one that did not. Results: Following implementation of the PGx result message, there was a decrease in patients reporting negative responses surrounding satisfaction in the return of their PGx results, with 39% responding negatively pre-implementation and 21% post-implementation. Conclusion: Satisfaction with the return of results improved following the implementation of a patient portal message.

Impact of transitioning to an active, noninterruptive CYP2C19/proton pump inhibitor alert on prescribing patterns.

PURPOSE: To compare rates of prescriber acceptance of interruptive and noninterruptive clinical decision support (CDS) alerts regarding potential diminished therapeutic effectiveness and safety risks associated with proton pump inhibitor (PPI) use in carriers of gene variants affecting cytochrome P450 (CYP) isozyme 2C19 metabolism. METHODS: A retrospective study was conducted at a large rural health system to examine different approaches to improving CDS alert acceptance while minimizing alert fatigue. Manual reviews were conducted to identify alerts regarding CYP2C19 metabolizer status displayed at the time of PPI ordering over 30-day periods before and after the transition from interruptive to noninterruptive CDS alert functionality. A chi-square test was conducted to analyze prescriber acceptance of CDS recommendations by alert modality and type of treatment modification. RESULTS: Overall, interruptive alerts had an acceptance rate of 18.6% (64/344), compared to 8.4% acceptance (30/357 alerts) for noninterruptive alerts (P ≤ 0.0001). Analysis of acceptance criteria -revealed the noninterruptive alert cohort had higher acceptance, as determined by documented medication dose adjustments, than the interruptive alert cohort (53.3% [16/30] and 4.7% [3/64], respectively). The difference in acceptance rates by CDS modality and treatment modification was statistically significant (P ≤ 0.00001). The predominant indication for PPI use was gastroesophageal reflux disease (GERD) in both cohorts. CONCLUSION: Interruptive alerts that actively influenced workflow had higher acceptance rates than noninterruptive alerts that served an informational purpose without a direct disruption of workflow. The study results suggest the utilization of noninterruptive alerts may be a beneficial tool for prompting clinicians to alter dosing regimens rather than transition to an alternative agent.

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes.

Metoprolol is a medication commonly utilized in select patients to achieve a reduction in heart rate, systolic blood pressure, or other indications. A majority of metoprolol metabolism occurs via CYP2D6. Decreased expression of the CYP2D6 enzyme increases the concentration of metoprolol. Current pharmacogenomics guidelines by the Dutch Pharmacogenomics Working Group recommend slower titrations and dose decreases to minimize adverse effects from poor metabolizers or normal metabolizers taking concomitant medications that are strong inhibitors of CYP2D6 (phenoconverters). This study aimed to evaluate adverse effects such as bradycardia, hypotension, and syncope in patients who are expected to have absent CYP2D6 enzyme activity due to drug-drug or drug-gene interactions. The secondary aims of this study were to evaluate heart rate measurements for the included participants. Retrospective data were collected for individuals with CYP2D6 genotyping results obtained for clinical purposes. Three categories (CYP2D6 normal metabolizers, poor metabolizers, and phenoconverters) were assigned. A total of 325 participants were included. There was no statistically significant difference found in the primary composite outcome between the three metabolizer groups (p = 0.054). However, a statistically significant difference was identified in the incidences of bradycardia between the poor metabolizers and the normal metabolizers or phenoconverters (p < 0.0001). The average heart rates were 2.8 beats per minute (bpm) and 2.6 bpm lower for the poor metabolizer and phenoconverter groups, respectively, compared to the normal metabolizers (p < 0.0001 for both comparisons). This study further supports the role of genetic testing in precision medicine to help individualize patient care as CYP2D6 poor metabolizers taking metoprolol were found to have an increase in bradycardia. Additional research is needed to clarify the dose relationship in this drug-gene interaction.

Impact of Automated Best Practice Advisories on Provider Response to CYP2C19 Genotyping Results for Patients on Clopidogrel.

ObjectiveThe study objective was to examine provider acceptance and genotyping responses to a best practice advisory (BPA) concerning clopidogrel and CYP2C19 intermediate and poor metabolizers within the context of a new pharmacogenomics program at a Midwestern health system. Other secondary objectives analyzed included appropriate BPA firing, the distribution of alleles in study population, indications for clopidogrel use, and impact of indication on therapy change. Methods: In this study, the progress of this program was assessed by quantifying how providers respond to BPAs generated in the electronic medical record (EMR), in the context of a single representative gene-drug-outcome relationship. Patient data was pulled via reports yielding patients with genotyped information in the EMR and cross-referenced with a report evaluating BPA firing occurrences. Results: By capturing antiplatelet therapy changes in response to CYP2C19 genotyping results, 37 patients were found that had 73 BPAs fire. Nine of those patients had alternative antiplatelet therapy ordered. Of these, 6 alternative antiplatelet therapies were ordered from the BPA. Conclusion: Providers utilized BPAs, but responded differently based on individual knowledge of genotypes and indications. Information obtained from this study can be used for provider education and as reference for future design and wording of BPAs.

Well-being Content Inclusion in Pharmacy Education Across the United States and Canada.

Objective. To describe the landscape of well-being content inclusion across schools and colleges of pharmacy in the United States and Canada through identification of content implementation, incorporation, and assessment.Methods. A cross-sectional survey was distributed to all accredited schools and colleges of pharmacy in the United States (n=143) and Canada (n=10). Survey questions included curricular and cocurricular timing, frequency, assessment strategies, and support for well-being initiatives, using a framework of eight dimensions (pillars) of wellness to categorize content.Results. Descriptive data analyses were applied to 99 completed surveys (65%), 89 (62%) in the United States and 10 (100%) in Canada. Well-being content was most prevalent within the cocurricular realm and incorporated into didactic and elective more than experiential curricula. The most content came from intellectual, emotional, and physical pillars, and the least content came from financial, spiritual, and environmental pillars. Less than 50% of schools and colleges of pharmacy include well-being within their strategic plans or core values. Funding is primarily at the level of the university (59%) or the school or college of pharmacy (59%). Almost half of respondents reported inclusion of some assessment, with a need for more training, expertise, and standardization.Conclusion. Survey results revealed a wide range of implementation and assessment of well-being programs across the United States and Canada. These results provide a reference point for the state of well-being programs that can serve as a call to action and research across the Academy.

Workforce Considerations When Building a Precision Medicine Program.

This paper describes one healthcare system's approach to strategically deploying genetic specialists and pharmacists to support the implementation of a precision medicine program. In 2013, Sanford Health initiated the development of a healthcare system-wide precision medicine program. Here, we report the necessary staffing including the genetic counselors, genetic counseling assistants, pharmacists, and geneticists. We examined the administrative and electronic medical records data to summarize genetic referrals over time as well as the uptake and results of an enterprise-wide genetic screening test. Between 2013 and 2020, the number of genetic specialists employed at Sanford Health increased by 190%, from 10.1 full-time equivalents (FTEs) to 29.3 FTEs. Over the same period, referrals from multiple provider types to genetic services increased by 423%, from 1438 referrals to 7517 referrals. Between 2018 and 2020, 11,771 patients received a genetic screening, with 4% identified with potential monogenic medically actionable predisposition (MAP) findings and 95% identified with at least one informative pharmacogenetic result. Of the MAP-positive patients, 85% had completed a session with a genetics provider. A strategic workforce staffing and deployment allowed Sanford Health to manage a new genetic screening program, which prompted a large increase in genetic referrals. This approach can be used as a template for other healthcare systems interested in the development of a precision medicine program.

Implementation and evaluation of a student scholarship program to increase care initiatives in rural pharmacies.

INTRODUCTION: Availability of patient care services in rural areas is often lacking, which can reduce access to care for patients living in these areas. Patient care within community pharmacies is vital to care access in rural areas, but expanding pharmacy services can often be challenging. Pharmacy students, especially those on advanced pharmacy practice experiences, are positioned to make an impact on sites. METHODS: The objective of this study was to describe the implementation, evaluation, and impact of a student scholarship program designed to increase patient care initiatives in rural community pharmacies. Scholarships were provided to students to expand patient care initiatives targeting chronic disease in select rural community pharmacies. Before and after participating in the scholarship program, students completed a survey assessing their perceived ability and confidence to initiate new patient care activities. In addition, patient care services provided by students were tracked and reported cumulatively. RESULTS: During the first year of implementation, 24 student scholarship rotations were completed. Throughout the 24 rotations, 369 patients were screened for prediabetes, 391 were screened for hypertension, and 552 patients were screened for immunizations. Of the 27 items presented in the survey, 20 items showed a mean statistically significant change indicating an increase in student confidence in leading, developing, and performing patient care activities. CONCLUSIONS: A student scholarship program designed to increase patient care initiatives in rural community pharmacies led to new patient care services in rural areas and increased student confidence in leading, developing, and expanding upon patient care activities.

A Mixed-Methods Protocol to Identify Best Practices for Implementing Pharmacogenetic Testing in Clinical Settings.

Using a patient's genetic information to inform medication prescriptions can be clinically effective; however, the practice has not been widely implemented. Health systems need guidance on how to engage with providers to improve pharmacogenetic test utilization. Approaches from the field of implementation science may shed light on the complex factors affecting pharmacogenetic test use in real-world settings and areas to target to improve utilization. This paper presents an approach to studying the application of precision medicine that utilizes mixed qualitative and quantitative methods and implementation science frameworks to understand which factors or combinations consistently account for high versus low utilization of pharmocogenetic testing. This approach involves two phases: (1) collection of qualitative and quantitative data from providers-the cases-at four clinical institutions about their experiences with, and utilization of, pharmacogenetic testing to identify salient factors; and (2) analysis using a Configurational Comparative Method (CCM), using a mathematical algorithm to identify the minimally necessary and sufficient factors that distinguish providers who have higher utilization from those with low utilization. Advantages of this approach are that it can be used for small to moderate sample sizes, and it accounts for conditions found in real-world settings by demonstrating how they coincide to affect utilization.

Progression of precision statin prescribing for reduction of statin-associated muscle symptoms.

Background: Statins are among the most commonly prescribed medications, and improve patient outcomes by lowering cholesterol levels, but also have side effects. Variations in statin response can be attributed to a handful of factors that include pharmacogenetics. Methods: While not a true review article, this work was written using various search engines and terms and previous and newly published Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statins to provide a historical perspective in addition to the current status of statin-related pharmacogenetics and future perspectives. Results: This article provides historical background on statins and associated adverse effects, reviews pharmacogenetic implications, applies clinical decision support, incorporates the latest CPIC guidelines and addresses future implications. Conclusion: Statins are a beneficial medication, but not without risk. Pharmacogenomics can help mitigate some risk factors. Clinical decision support, implementation, research and guidelines will continue to influence statin prescribing.

Pharmacogenetic Review: Germline Genetic Variants Possessing Increased Cancer Risk With Clinically Actionable Therapeutic Relationships.

As our understanding of genomics and genetic testing continues to advance, the personalization of medical decision making is progressing simultaneously. By carefully crafting medical care to fit the specific needs of the individual, patients can experience better long-term outcomes, reduced toxicities, and improved healthcare experiences. Genetic tests are frequently ordered to help diagnose a clinical presentation and even to guide surveillance. Through persistent investigation, studies have begun to delineate further therapeutic implications based upon unique relationships with genetic variants. In this review, a pre-emptive approach is taken to understand the existing evidence of relationships between specific genetic variants and available therapies. The review revealed an array of diverse relationships, ranging from well-documented clinical approaches to investigative findings with potential for future application. Therapeutic agents identified in the study ranged from highly specific targeted therapies to agents possessing similar risk factors as a genetic variant. Working in conjunction with national standardized treatment approaches, it is critical that physicians appropriately consider these relationships when developing personalized treatment plans for their patients.

Best-worst scaling methodology to evaluate constructs of the Consolidated Framework for Implementation Research: application to the implementation of pharmacogenetic testing for antidepressant therapy.

BACKGROUND: Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best-worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. METHODS: We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. RESULTS: Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. CONCLUSIONS: This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.

Pharmacists Leading the Way to Precision Medicine: Updates to the Core Pharmacist Competencies in Genomics.

Genomics is becoming an increasingly important part of health care, and pharmacists are well-positioned to be practice-based leaders in pharmacogenomics and precision medicine. Competencies available through the Genetics/Genomics Competency Center provide a framework for pharmacogenomics instruction in both pharmacy school curricula and continuing education programs. Given the significant advancements in pharmacogenomics over the past decade, the 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group updated the pharmacist competencies. The process used a systematic approach which included mapping pharmacogenomics-specific competencies to the entrustable professional activities for pharmacists and seeking consensus from key stakeholders. The result is an expansion to 30 competencies that reflect the contemporary roles pharmacists play in the application of pharmacogenomics in clinical practice. When implemented into curricula, these competencies will ensure that learners are "practice ready" to integrate pharmacogenomics into patient care. Additional postgraduate training is needed for advanced roles in pharmacogenomics implementation, education, and research.