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1.
Clin Pharmacol Ther ; 2018 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-30506689

RESUMO

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

2.
JACC Basic Transl Sci ; 3(4): 545-549, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175278

RESUMO

The U.S. Food and Drug Administration recently marked 10 years since first updating the labeling for warfarin (often referred to as the "poster child" of pharmacogenomics) to include information regarding the potential impact of CYP2C9 and VKORC1 genetic variation on warfarin dosing requirements and risks. Herein, we opine on the experience updating the warfarin labeling, highlighting more generally the enabling factors and challenges encountered when considering incorporation of pharmacogenomic information into the prescribing recommendations for already approved drugs. We also provide a historical perspective of implemented changes in regulatory policies related to personalized medicine.

3.
Pharmacotherapy ; 37(9): 1000-1004, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28605049

RESUMO

Advancing the use of biomarkers and pharmacogenomics has been a key priority area for the U.S. Food and Drug Administration (FDA). The FDA offers prescribing recommendations to manage ~100 gene-drug interactions, and multiple institutions around the United States and abroad have incorporated genomic testing into patient care. However, the penetration of pharmacogenomic testing remains incomplete. In this perspective, we summarize the evidence streams to support the clinical utility of pharmacogenomic testing and its transition into clinical practice.


Assuntos
Ensaios Clínicos como Assunto/métodos , Testes Farmacogenômicos/métodos , United States Food and Drug Administration , Humanos , Farmacogenética/métodos , Farmacogenética/tendências , Testes Farmacogenômicos/tendências , Estados Unidos , United States Food and Drug Administration/tendências
4.
Mol Genet Genomic Med ; 4(5): 513-20, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27652279

RESUMO

INTRODUCTION: African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized. METHODS: We performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP). RESULTS: In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10). CONCLUSIONS: We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.

5.
Pharmacogenomics ; 16(3): 217-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25712185

RESUMO

AIM: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans. METHODS: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. RESULTS: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. CONCLUSION: African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014.


Assuntos
Afro-Americanos/genética , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Anticoagulantes/sangue , Superfície Corporal , Peso Corporal , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Vitamina K Epóxido Redutases/genética , Varfarina/sangue
6.
Transl Res ; 165(6): 651-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25499099

RESUMO

Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans (AAs). In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics and CYP2C9 expression in 63 AA patients and 32 AA liver tissues, respectively. We found oral clearance of S-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared with wild-type homozygotes (3.73 ± 1.46 vs 2.95 ± 1.39 mL/min; P = 0.04). CYP2C9 messenger RNA expression in liver tissue was also higher among A/T and T/T genotypes compared with A/A (P < 0.02). Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/genética , Polimorfismo de Nucleotídeo Único , Varfarina/farmacocinética , Adulto , Idoso , Feminino , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Farmacogenética
7.
Pharmacogenet Genomics ; 25(2): 73-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25461246

RESUMO

OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. METHODS: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. RESULTS: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. CONCLUSION: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.


Assuntos
Afro-Americanos/genética , Algoritmos , Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Cálculos da Dosagem de Medicamento , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único , Varfarina/administração & dosagem , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
8.
Pharmacogenomics ; 15(7): 909-14, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24956244

RESUMO

We describe a 64-year-old male of Indian descent with a history of atrial fibrillation who was started on warfarin after hospital admission for acute stroke. He received genotype-guided warfarin dosing as per the standard-of-care at our hospital, with daily dose recommendations provided by the pharmacogenetics service. Genotyping revealed the rare CYP2C9*1/*14 genotype and warfarin insensitive VKORC1 -1639GG and CYP4F2 433Met/Met genotypes. The patient received an initial warfarin loading dose of 4 mg for 2 days, followed by 2-3 mg/day for the following 11 days. He reached a therapeutic international normalized ratio on day 5, which was maintained over the following week. This report adds to the limited data of the effects of the CYP2C9*14 allele on warfarin dose requirements.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Citocromo P-450 CYP2C9/genética , Relação Dose-Resposta a Droga , Varfarina/administração & dosagem , Alelos , Fibrilação Atrial/induzido quimicamente , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Varfarina/efeitos adversos
9.
Pharmacotherapy ; 34(2): 166-84, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24523097

RESUMO

Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to guide pharmacotherapy used to treat psychiatric and neurological (neuropsychiatric) conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of existing genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for determining the starting and target doses, as well as drug interaction potential, for a number of other drugs. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.


Assuntos
Testes Genéticos/métodos , Farmacogenética/métodos , Psicotrópicos/uso terapêutico , Fármacos do Sistema Nervoso Central/uso terapêutico , Interações de Medicamentos , Rotulagem de Medicamentos , Humanos , Guias de Prática Clínica como Assunto
10.
Am J Pharm Educ ; 77(8): 175, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24159216

RESUMO

OBJECTIVE: To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. DESIGN: First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. ASSESSMENT: Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. CONCLUSION: A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.


Assuntos
Bolsas de Estudo , Farmacogenética , Residências em Farmácia , Estudantes de Farmácia , Avaliação Educacional , Humanos , Varfarina/uso terapêutico
11.
BMC Genomics ; 14 Suppl 3: S11, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23819817

RESUMO

BACKGROUND: Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations. RESULTS: Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association. CONCLUSIONS: Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.


Assuntos
Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Redes e Vias Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Varfarina/metabolismo , Afro-Americanos/genética , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Oxigenases de Função Mista/genética , Vitamina K Epóxido Redutases , Varfarina/administração & dosagem
12.
Pharmacotherapy ; 33(11): 112017 Apr, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23864527

RESUMO

STUDY OBJECTIVE: To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. DESIGN: Prospective observational study. SETTING: A 438-bed tertiary care hospital affiliated with a large academic institution. PATIENTS: Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. INTERVENTION: All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. CONCLUSION: Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff.


Assuntos
Sistemas de Registro de Ordens Médicas , Farmacogenética/métodos , Serviço de Farmácia Hospitalar/métodos , Varfarina/efeitos adversos , Adulto , Idoso , Registros Eletrônicos de Saúde/normas , Estudos de Viabilidade , Feminino , Humanos , Masculino , Sistemas de Registro de Ordens Médicas/normas , Pessoa de Meia-Idade , Farmacogenética/normas , Serviço de Farmácia Hospitalar/normas , Estudos Prospectivos , Varfarina/uso terapêutico
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