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PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.
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Deficiencia de Dihidropirimidina Deshidrogenasa , Dihidrouracilo Deshidrogenasa (NADP) , Humanos , Estados Unidos , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Deficiencia de Dihidropirimidina Deshidrogenasa/diagnóstico , Neoplasias/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Encuestas y Cuestionarios , Fluorouracilo/efectos adversos , Fluorouracilo/administración & dosificaciónRESUMEN
Aim: Identify oncology healthcare providers' attitudes toward barriers to and use cases for pharmacogenomic (PGx) testing and implications for prescribing anticancer and supportive care medications. Materials & methods: A questionnaire was designed and disseminated to 71 practicing oncology providers across the MedStar Health System. Results: 25 of 70 (36%) eligible oncology providers were included. 88% were aware of PGx testing and 72% believed PGx can improve care. Of providers who had ordered a medication with PGx implications in the past month, interest in PGx for anticancer (90-100%) and supportive care medications (>75%) was high. Providers with previous PGx education were more likely to have ordered a test (odds ratio: 7.9; 95% CI: 1.1-56; p = 0.0394). Conclusion: Oncology provider prescribing practices and interest in PGx suggest opportunities for implementation.
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Farmacogenética , Pruebas de Farmacogenómica , Humanos , Farmacogenética/educación , Oncología MédicaRESUMEN
Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Farmacogenética/educación , Fármacos Cardiovasculares/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Personal de SaludRESUMEN
Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.
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Dihidrouracilo Deshidrogenasa (NADP) , Fluorouracilo , Estados Unidos , Humanos , Fluorouracilo/efectos adversos , United States Food and Drug Administration , Dihidrouracilo Deshidrogenasa (NADP)/genética , Capecitabina/efectos adversos , Genotipo , AntimetabolitosRESUMEN
Patients experience interindividual variation in response to analgesics, which may be partially explained by genetics. This commentary discusses a recently published trial on COMT genotype and opioid dose requirements and describes the potential role for COMT and other genes (eg, CYP2D6) on opioid therapy and the current evidence for germline pharmacogenetics and resources for opioid pharmacogenetics.
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Dolor en Cáncer , Neoplasias , Humanos , Manejo del Dolor , Farmacogenética , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/genética , Oxicodona/uso terapéutico , Morfina/uso terapéutico , Analgésicos Opioides/uso terapéutico , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Genotipo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/uso terapéuticoRESUMEN
Clinical decision support (CDS) is often cited as an essential part of pharmacogenomics (PGx) implementations. A multitude of strategies are available; however, it is unclear which strategies are effective and which metrics are used to quantify clinical utility. The objective of this scoping review was to aggregate previous studies into a cohesive depiction of the current state of PGx CDS implementations and identify areas for future research on PGx CDS. Articles were included if they (i) described electronic CDS tools for PGx and (ii) reported metrics related to PGx CDS. Twenty of 3,449 articles were included and provided data on PGx CDS metrics from 15 institutions, with 93% of programs located at academic medical centers. The most common tools in CDS implementations were interruptive post-test alerts. Metrics for clinical response and alert response ranged from 12-73% and 21-98%, respectively. Few data were found on changes in metrics over time and measures that drove the evolution of CDS systems. Relatively few data were available regarding support of optimal approaches for PGx CDS. Post-test alerts were the most widely studied approach, and their effectiveness varied greatly. Further research on the usability, effectiveness, and optimization of CDS tools is needed.
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Sistemas de Apoyo a Decisiones Clínicas , Sistemas de Entrada de Órdenes Médicas , Humanos , Farmacogenética , Registros Electrónicos de Salud , Programas InformáticosRESUMEN
Ineffective pain control is the most commonly cited reason for misuse of prescription opioids and is influenced by genetics. In particular, the gene encoding the CYP2D6 enzyme, which metabolizes some of the most commonly prescribed opioids (e.g., tramadol, hydrocodone) to their more potent forms, is highly polymorphic and can lead to reduced concentrations of the active metabolites and decreased opioid effectiveness. Consideration of the CYP2D6 genotype may allow for predicting opioid response and identifying patients who are likely to respond well to lower potency opioids as well as those who may derive greater pain relief from non-opioid analgesics versus certain opioids. There is emerging evidence that a CYP2D6-guided approach to pain management improves pain control and reduces opioid consumption and thus may be a promising means for combating opioid misuse. Clinical practice guidelines are available for select opioids and other analgesics to support medication and dose selection based on pharmacogenetic data. This article describes the evidence supporting genotype-guided pain management as a means of improving pain control and reducing opioid misuse and clinical recommendations for genotype-guided analgesic prescribing. In addition, a "how to" guide using patient case examples is provided to demystify the process for implementing pharmacogenetics-guided pain management in order to optimize analgesia and minimize adverse effects. Optimizing pain management through genotype-guided approaches may ultimately provide safer and more effective therapy for pain control while decreasing the risk for opioid misuse.
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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.
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Aim: To evaluate the effect of pharmacogenomics (PGx) education for pharmacists. Materials & Methods: Three-part weekly webinar series occurred in 2021. Pharmacists were assessed on their PGx knowledge at baseline and after each webinar. The primary end point was a change in the percent of correct responses between the baseline and week 1 assessment. Secondary end points included change in knowledge at weeks 4-8 and change in self-efficacy. Results: In total, 19 of 58 participants were eligible for the primary analysis, which showed an average improvement of 37% (p < 0.0001). Knowledge remained consistent between week 1 and weeks 4-8. Average self-efficacy increased (p < 0.0001) and was maintained at weeks 4-8. Conclusion: The PGx webinar series resulted in a lasting improvement in PGx knowledge and self-efficacy.
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Educación en Farmacia , Farmacogenética/educación , Rendimiento Académico , Adulto , Educación a Distancia/métodos , Educación en Farmacia/métodos , Evaluación Educacional , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Farmacéuticos/estadística & datos numéricos , Adulto JovenRESUMEN
Clinical decision support (CDS) is an essential part of any pharmacogenomics (PGx) implementation. Increasingly, institutions have implemented CDS tools in the clinical setting to bring PGx data into patient care, and several have published their experiences with these implementations. However, barriers remain that limit the ability of some programs to create CDS tools to fit their PGx needs. Therefore, the purpose of this review is to summarize the types, functions, and limitations of PGx CDS currently in practice. Then, we provide an approachable step-by-step how-to guide with a case example to help implementers bring PGx to the front lines of care regardless of their setting. Particular focus is paid to the five "rights" of CDS as a core around designing PGx CDS tools. Finally, we conclude with a discussion of opportunities and areas of growth for PGx CDS.
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Sistemas de Apoyo a Decisiones Clínicas , Farmacogenética , Registros Electrónicos de Salud , Humanos , Atención al Paciente , Programas InformáticosRESUMEN
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.
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Antidepresivos/uso terapéutico , Farmacogenética , Pruebas de Farmacogenómica , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Humanos , Farmacogenética/métodosRESUMEN
PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
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Farmacogenética , Pruebas de Farmacogenómica , Prescripciones de Medicamentos , Pruebas Genéticas , Humanos , Farmacogenética/métodos , Medicina de Precisión/métodosRESUMEN
CYP2D6 genotype is increasingly being integrated into practice to guide prescribing of certain medications. The CYP2D6 drug metabolizing enzyme is susceptible to inhibition by concomitant drugs, which can lead to a clinical phenotype that is different from the genotype-based phenotype, a process referred to as phenoconversion. Phenoconversion is highly prevalent but not widely integrated into practice because of either limited experience on how to integrate or lack of knowledge that it has occurred. We built a calculator tool to help clinicians integrate a standardized method of assessing CYP2D6 phenoconversion into practice. During tool-building, we identified several clinical factors that need to be considered when implementing CYP2D6 phenoconversion into clinical practice. This tutorial shares the steps that the University of Florida Health Precision Medicine Program took to build the calculator tool and identified clinical factors to consider when implementing CYP2D6 phenoconversion in clinical practice.
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Citocromo P-450 CYP2D6/genética , Genotipo , Humanos , Inactivación Metabólica/genética , Farmacogenética/métodos , Fenotipo , Medicina de Precisión/métodosRESUMEN
Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre-survey and post-survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype-guided recommendations were provided to physicians for their consideration in clinical decisions. Patient-reported symptom severity and antidepressant-related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real-world clinical setting, which may inform the methodology of a larger trial focused on outcomes.
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Antidepresivos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Trastornos Mentales/tratamiento farmacológico , Pruebas de Farmacogenómica/estadística & datos numéricos , Medicina de Precisión/métodos , Adolescente , Instituciones de Atención Ambulatoria/estadística & datos numéricos , Niño , Toma de Decisiones Clínicas/métodos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Estudios de Factibilidad , Femenino , Humanos , Masculino , Trastornos Mentales/genética , Variantes Farmacogenómicas , Proyectos Piloto , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios/estadística & datos numéricosRESUMEN
Aims: Identify the attitudes and interests of primary care providers (PCPs) in applying clinical pharmacogenomics (PGx) test results. Materials & methods: A questionnaire was designed and then disseminated to PCPs across the MedStar Health System. Results: Ninety of 312 (29%) PCPs responded and were included in analyses. Seventy-six (84%) had heard of PGx and 12 (13%) previously ordered PGx testing. Most, 68 (76%), believed PGx can improve care; however, a minority, 23 (26%), reported confidence in using PGx in prescribing decisions. Sixty-four (70%) wanted a pharmacist consultation. PCPs desired PGx for antidepressants (75%), proton pump inhibitors (72%) and other medications. Conclusion: Most PCPs felt unprepared to interpret PGx results and desired pharmacist consultations. These data can inform future PGx implementations with PCPs.
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Actitud del Personal de Salud , Personal de Salud/psicología , Pruebas de Farmacogenómica/métodos , Atención Primaria de Salud/métodos , Encuestas y Cuestionarios , Femenino , Humanos , Masculino , Enfermeras Practicantes/psicología , Farmacogenética/métodos , Asistentes Médicos/psicología , Médicos de Atención Primaria/psicología , Medicina de Precisión/psicologíaRESUMEN
Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist's effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist-physician collaboration.
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The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels for area under the plasma concentration-time curve (AUC) fold-changes caused by inhibitors in humans and identified 89 inhibitor-substrate pairs. Observed AUC fold-change of the substrate was used to create an observed inhibitor classification per FDA-defined AUC fold-change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.