RESUMEN
Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.
Asunto(s)
Etiquetado de Medicamentos/métodos , Preparaciones Farmacéuticas/química , Farmacogenética/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Pruebas de Farmacogenómica/métodos , SuizaRESUMEN
BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.
Asunto(s)
Algoritmos , Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Oxigenasas de Función Mixta/genética , Farmacogenética , Warfarina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Relación Normalizada Internacional , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Vitamina K Epóxido Reductasas , Adulto JovenRESUMEN
Recent advances in high-throughput genotyping and phenotyping have accelerated the creation of pharmacogenomic data. Consequently, the community requires standard formats to exchange large amounts of diverse information. To facilitate the transfer of pharmacogenomics data between databases and analysis packages, we have created a standard XML (eXtensible Markup Language) schema that describes both genotype and phenotype data as well as associated metadata. The schema accommodates information regarding genes, drugs, diseases, experimental methods, genomic/RNA/protein sequences, subjects, subject groups, and literature. The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB; www.pharmgkb.org) has used this XML schema for more than 5 years to accept and process submissions containing more than 1,814,139 SNPs on 20,797 subjects using 8,975 assays. Although developed in the context of pharmacogenomics, the schema is of general utility for exchange of genotype and phenotype data. We have written syntactic and semantic validators to check documents using this format. The schema and code for validation is available to the community at http://www.pharmgkb.org/schema/index.html (last accessed: 8 October 2007).
Asunto(s)
Bases de Datos Genéticas , Lenguajes de Programación , Genotipo , Humanos , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , Programas InformáticosRESUMEN
Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well-known gene-drug pairs. Published recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.
Asunto(s)
Farmacogenética , Guías de Práctica Clínica como Asunto , Medicina de Precisión , Pruebas Genéticas/métodos , Humanos , Países Bajos , Farmacogenética/métodos , Farmacogenética/normas , Pautas de la Práctica en Medicina , Medicina de Precisión/métodos , Medicina de Precisión/normas , Investigación Biomédica Traslacional/métodos , Investigación Biomédica Traslacional/normas , Estados UnidosRESUMEN
The Pharmacogenetics and Pharmacogenomics Knowledge Base, PharmGKB (http://www.pharmgkb.org), curates pharmacogenetic and pharmacogenomic information to generate knowledge concerning the relationships among genes, drugs, and diseases, and the effects of gene variation on these relationships. PharmGKB curators collect information on genotype-phenotype relationships both from the literature and from the deposition of primary research data into our database. Their goal is to catalyze pharmacogenetic and pharmacogenomic research.
Asunto(s)
Bases de Datos Genéticas , Farmacogenética/organización & administración , Investigación Biomédica/organización & administración , Quimioterapia , Variación Genética , Genoma Humano , Genotipo , Humanos , FenotipoRESUMEN
The pharmacogenetics and pharmacogenomics knowledge base (PharmGKB, http://www.pharmgkb.org) is a publicly available internet resource dedicated to the integration, annotation, and aggregation of pharmacogenomic knowledge. PharmGKB is a repository for pharmacogenetic and pharmacogenomic data, and curators provide integrated knowledge in terms of gene summaries, pathways, and annotated literature. Although PharmGKB is primarily directed toward catalyzing new research, it also has utility as a source of information for education about pharmacogenomics.
Asunto(s)
Instrucción por Computador , Bases de Datos como Asunto , Internet , Farmacogenética/educación , Fármacos Cardiovasculares/uso terapéutico , Gráficos por Computador , Genotipo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Humanos , Selección de Paciente , Fenotipo , Integración de SistemasRESUMEN
Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
Asunto(s)
Citocromo P-450 CYP2C19/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Técnicas de Genotipaje/métodos , Tasa de Depuración Metabólica/fisiología , Voriconazol , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Selección de Paciente , Variantes Farmacogenómicas/genética , Medición de Riesgo/métodos , Voriconazol/farmacocinética , Voriconazol/uso terapéuticoRESUMEN
The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.
Asunto(s)
Investigación Biomédica/organización & administración , Farmacogenética/organización & administración , Medicina de Precisión/métodos , Investigación Biomédica Traslacional/organización & administración , HumanosRESUMEN
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Asunto(s)
Anticoagulantes/administración & dosificación , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Adulto , Niño , Relación Dosis-Respuesta a Droga , Genotipo , Humanos , Farmacogenética , Guías de Práctica Clínica como AsuntoRESUMEN
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.
Asunto(s)
Atención a la Salud/organización & administración , Farmacogenética/métodos , Guías de Práctica Clínica como Asunto , Investigación Biomédica Traslacional/organización & administración , Alelos , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMEN
Significant advances have been made in the clinical implementation of pharmacogenomics in recent years with tools for clinical decision support (CDS) being developed and integrated in the electronic health record (EHR). In this issue, the article by Hussain et al. describes the creation of a disease-drug association tool that enables providers to search by disease indications to receive a list of treatment options marked with pharmacogenomics annotations at the point of prescribing.
Asunto(s)
Bases de Datos Farmacéuticas , Sistemas de Apoyo a Decisiones Clínicas , Farmacogenética/métodos , Pautas de la Práctica en Medicina , Registros Electrónicos de Salud/organización & administración , HumanosRESUMEN
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).
Asunto(s)
Alopurinol/administración & dosificación , Biomarcadores Farmacológicos , Guías como Asunto/normas , Antígenos HLA-B/genética , Esquema de Medicación , Genotipo , HumanosRESUMEN
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
Asunto(s)
Sulfato de Atazanavir/efectos adversos , Glucuronosiltransferasa/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/efectos adversos , Hiperbilirrubinemia/inducido químicamente , Ictericia/inducido químicamente , Hígado/efectos de los fármacos , Farmacogenética/normas , Predisposición Genética a la Enfermedad , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Hiperbilirrubinemia/enzimología , Hiperbilirrubinemia/genética , Ictericia/enzimología , Ictericia/genética , Hígado/enzimología , Fenotipo , Medición de Riesgo , Factores de RiesgoRESUMEN
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Asunto(s)
Alelos , Pruebas Genéticas/normas , Farmacogenética/normas , Terminología como Asunto , Genes , Pruebas Genéticas/tendencias , Variación Genética , Humanos , Farmacogenética/tendencias , Medicina de PrecisiónRESUMEN
The relationship between structure and the Michaelis-Menten constants (Km) for the papain hydrolysis of a series of 37 N-benzoylglycine esters was investigated. The series studied comprises a wide range of aromatic and aliphatic esters with a 5000-fold variation in their Km constants and essentially constant kcat values. It was found that the variation in the Km constants could be rationalized by the following quantitative structure-activity relationship (QSAR): log 1/Km = 8.13F + 0.33Z + 1.27II3' + 1.95. In this equation F is the field inductive parameter, II3' is the hydrophobic constant for the more lipophilic of the two possible meta substituents and Z is the Van der Waals distance from oxygen through the end of the molecule, in the direction of the 4 position of the aromatic ester moiety.
Asunto(s)
Glicina/análogos & derivados , Papaína/metabolismo , Simulación por Computador , Glicina/metabolismo , Hidrólisis , Cinética , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
The role of hydrophobic and electronic effects on the kinetic constants kcat and Km for the papain hydrolysis of a series of 22 substituted N-benzoylglycine pyridyl esters was investigated. The series studied comprises a wide variety of substituents on the N-benzoyl ring, with about a 300,000-fold range in their hydrophobicities, and 2.1-fold range in their electronic Hammet constants (sigma). It was found that the variation in the log kcat and log 1/Km constants could be explained by the following quantitative-structure activity relationships (QSAR): log 1/Km = 0.40 pi 4 + 4.40 and log 1/kcat = 0.45 sigma + 0.18. The substituent constant, pi 4, is the hydrophobic parameter for the 4-N-benzoyl substituents. QSAR analysis of two smaller sets of glycine phenyl and methyl esters produced similar results. A clear separation of the substituent effects indicates that in the case of these particular esters, acylation appears to be the rate limiting catalytic step.
Asunto(s)
Hipuratos/química , Papaína/química , Catálisis , Electroquímica , Hidrólisis , Cinética , Relación Estructura-ActividadRESUMEN
As pharmacogenomics becomes integrated into clinical practice, curation of published studies becomes increasingly important. At the Pharmacogenomics Knowledgebase (PharmGKB; www.pharmgkb.org), pharmacogenetic associations reported in published articles are manually curated and evaluated. Standard terminologies are used, making findings uniform and unambiguous. Lack of information, clarity, or standards in the original report can make it difficult or impossible to curate. We provide 10 rules to help authors ensure that their results are accurately captured and integrated.
Asunto(s)
Bases de Datos como Asunto/normas , Bases del Conocimiento , Farmacogenética/normas , HumanosRESUMEN
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
Asunto(s)
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Cálculo de Dosificación de Drogas , Farmacogenética/normas , Polimorfismo Genético , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Biotransformación , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Genotipo , Humanos , Seguridad del Paciente , Fenotipo , Medición de Riesgo , Factores de Riesgo , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinéticaRESUMEN
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).