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.

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.

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.

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.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

The effect of medication reconciliation on generating an accurate medication list in a pharmacogenomics practice.

Background: Medication reconciliation is recognized as a critically important medication safety element and a key initiative by multiple organizations. Within our precision medicine program, accurate medication lists are essential to our ability to make specific medication recommendations based on pharmacogenetic results. Our study aimed to identify discrepancies within the patient's medication list to improve medication management via genetic factors through a pharmacy team-based approach. Methods: A dedicated team of pharmacists and trained student pharmacists conducted telephone interviews to complete medication reconciliation for individuals enrolled in our precision medicine preemptive screening program. Medication list discrepancies were tracked as well as if pharmacogenetic consults were altered by findings during the telephone interviews. Results: Medication reconciliation was completed on 465 participants who had recently received or were awaiting pharmacogenetic testing. We found similar results to previously described rates of medication list discrepancies with an average of 4.9 medication discrepancies per patient as well as greater than 90% of individuals having at least one medication discrepancy. Pharmacogenetic recommendations for 20 individuals (4.3%) required adjustment following medication reconciliation. Conclusions: This pilot program supports the value of a dedicated team for medication reconciliation and the importance of accurate medication lists to optimize precision medicine programs.

Malignant hyperthermia susceptibility: utilization of genetic results in an electronic medical record to increase safety.

Aim: This manuscript describes implementation of clinical decision support for providers concerned with perioperative complications of malignant hyperthermia susceptibility. Materials & methods: Clinical decision support for malignant hyperthermia susceptibility was implemented in 2018 based around our pre-emptive genotyping platform. We completed a brief descriptive review of patients who underwent pre-emptive testing, focused particularly on RYR1 and CACNA1S genes. Results: To date, we have completed pre-emptive genetic testing on more than 10,000 patients; 13 patients having been identified as a carrier of a pathogenic or likely pathogenic variant of RYR1 or CACNA1S. Conclusion: An alert system for malignant hyperthermia susceptibility - as an extension of our pre-emptive genomics platform - was implemented successfully. Implementation strategies and lessons learned are discussed herein.