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1.
Clin Pharmacol Ther ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910286

RESUMO

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.

2.
Clin Transl Sci ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961467

RESUMO

Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

4.
Genet Med ; 21(10): 2255-2263, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30894703

RESUMO

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

5.
Genet Med ; 21(10): 2264-2274, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30926959

RESUMO

PURPOSE: Incorporating a patient's genotype into the clinical decision-making process is one approach to precision medicine. The University of Florida (UF) Health Precision Medicine Program is a pharmacist-led multidisciplinary effort that has led the clinical implementation of six gene-drug(s) pairs to date. This study focuses on the challenges encountered and lessons learned with implementing pharmacogenetic testing for three of these: CYP2D6-opioids, CYP2D6/CYP2C19-selective serotonin reuptake inhibitors, and CYP2C19-proton pump inhibitors within six pragmatic clinical trials at UF Health and partners. METHODS: We compared common measures collected within each of the pharmacogenetic implementations as well as solicited feedback from stakeholders to identify challenges, successes, and lessons learned. RESULTS: We identified several challenges related to trial design and implementation, and learned valuable lessons. Most notably, case discussions are effective for prescriber education, prescribers need clear concise guidance on genotype-based actions, having genotype results available at the time of the patient-prescriber encounter helps optimize the ability to act on them, children prefer noninvasive sample collection, and study participants are willing to answer patient-reported outcomes questionnaires if they are not overly burdensome, among others. CONCLUSION: The lessons learned from implementing three gene-drug pairs in ambulatory care settings will help shape future pharmacogenetic clinical trials and clinical implementations.

6.
Genet Med ; 21(8): 1842-1850, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30670877

RESUMO

PURPOSE: CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control. METHODS: Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures. RESULTS: On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540). CONCLUSION: These data support the potential benefits of CYP2D6-guided pain management.


Assuntos
Analgésicos Opioides/administração & dosagem , Citocromo P-450 CYP2D6/genética , Manejo da Dor/métodos , Dor/tratamento farmacológico , Adulto , Analgésicos Opioides/efeitos adversos , Codeína/administração & dosagem , Codeína/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/genética , Dor/patologia , Farmacogenética , Polimorfismo Genético , Medicina de Precisão
7.
Per Med ; 15(2): 117-126, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29714124

RESUMO

There is growing experience translating genomic data into clinical practice, as seen with the Implementing GeNomics In pracTicE (IGNITE) network. A primary example is the influence of CYP2D6 genotype on the beneficial and adverse effects of some opioids. Clinical recommendations exist to guide drug therapy based on CYP2D6 genotype for codeine, tramadol, oxycodone and hydrocodone, although the level of supporting evidence differs by drug. Limited evidence also supports the use of genetic data to guide other medications in chronic pain therapy, including tricyclic antidepressants and celecoxib. Pragmatic clinical trial data are needed in this area to better understand the impact of diverse populations, therapeutic interventions and clinical care environments on genotype-guided drug therapy for chronic pain.


Assuntos
Manejo da Dor/métodos , Farmacogenética/métodos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Codeína/uso terapêutico , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Genômica/métodos , Genótipo , Humanos , Hidrocodona/uso terapêutico , Oxicodona/uso terapêutico , Polimorfismo Genético/genética , Medicina de Precisão/métodos , Tramadol/uso terapêutico
8.
J Transl Med ; 16(1): 92, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29642909

RESUMO

BACKGROUND: The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. METHODS: Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. RESULTS: In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele). CONCLUSION: These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7.


Assuntos
Citocromo P-450 CYP2C19/genética , Técnicas de Genotipagem , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/farmacologia , Clopidogrel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
9.
Clin Transl Sci ; 11(2): 175-181, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29351371

RESUMO

Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme). TPMT tests were most commonly ordered for gastroenterology, rheumatology, dermatology, and hematology/oncology patients (661 of 834 patients (79.2%); 580 outpatient vs. 293 inpatient; P < 0.0001). Thirty-nine patients had both genotype and enzyme tests (n = 2 discordant results). We observed significant differences between TPMT test use and characteristics in a diverse, multispecialty environment vs. a pediatric cancer setting, which led to unique implementation needs. As pharmacogenetic implementations expand, disseminating lessons learned in diverse, real-world environments will be important to support routine adoption.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Metiltransferases/genética , Neoplasias/tratamento farmacológico , Farmacogenética/métodos , Adulto , Fatores Etários , Antimetabólitos Antineoplásicos/normas , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Sistemas de Apoio a Decisões Clínicas , Ensaios Enzimáticos/métodos , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Comunicação Interdisciplinar , Masculino , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Neoplasias/genética , Educação de Pacientes como Assunto , Farmacêuticos , Fenótipo , Polimorfismo Genético , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos , Centros de Atenção Terciária
10.
JACC Cardiovasc Interv ; 11(2): 181-191, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29102571

RESUMO

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.


Assuntos
Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Testes Farmacogenômicos , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Tomada de Decisão Clínica , Clopidogrel/efeitos adversos , Resistência a Medicamentos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Farmacogenética , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
12.
Ecol Appl ; 16(4): 1608-18, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16937821

RESUMO

Annually emerging cicadas are a numerically and ecologically dominant species in Southwestern riparian forests. Humans have altered disturbance regimes that structure these forests such that floods are less common and wildfires occur more frequently than was historically the case. Impacts of these changes on primary consumers such as riparian cicadas are unknown. Because cicadas are consumed by a variety of animal species, disturbances that alter timing of their emergence or abundance could have consequences for species at higher trophic levels. We trapped emerging cicadas (Tibicen dealbatus) in burned and unburned riparian forest plots along the Middle Rio Grande in central New Mexico (USA) to determine effects of wildfire and vegetation structure on their density and phenology. We measured vegetation variables and soil temperature at cicada traps and related these variables to variation in emergence density and phenology. We also experimentally heated soil under emergence traps to examine the relationship between soil temperature and emergence phenology. Emergence density was similar in wildfire and unburned plots, though emergence date averaged earlier in wildfire plots and experimentally heated traps. We identified models containing cottonwood proximity (distance from the nearest cottonwood tree) and cottonwood canopy coverage as the most parsimonious explanations of emergence density at each trap. Model selection results were consistent with the literature and field observations that showed that cottonwood trees are an essential resource for T. dealbatus. Cottonwood canopy was also correlated with low soil temperatures, which are associated with later emergence dates. Failure of cottonwoods to reestablish following wildfire could result in cicadas emerging at lower densities and at earlier dates. For cicadas to emerge at densities and times that provide the greatest benefits to birds and other riparian-obligate secondary consumers, riparian forests should be protected from fire, and native vegetation in wildfire sites should be restored.


Assuntos
Ecossistema , Fogo , Hemípteros/fisiologia , Plantas , Árvores , Animais , Rios , Sudoeste dos Estados Unidos , Fatores de Tempo
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