RESUMEN
Introduction: Alzheimer's disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility.
Asunto(s)
Enfermedad de Alzheimer/genética , Disfunción Cognitiva/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Anciano , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Ensayos Clínicos como Asunto , Disfunción Cognitiva/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Herencia Multifactorial/genética , Pruebas Neuropsicológicas , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
BACKGROUND: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. OBJECTIVES: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). METHODS: Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). RESULTS: Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%-50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%-24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10-5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. CONCLUSIONS: This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.
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Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Glucuronosiltransferasa/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Humanos , PiridonasRESUMEN
GlaxoSmithKline (GSK) conducted pharmacogenetic (PGx) analyses to determine whether genetic variants influence response to belimumab treatment in patients with systemic lupus erythematosus (SLE). We conducted an exploratory genome-wide meta-analysis (GWAS) of 10.9 million genetic variants and the efficacy data from 816 belimumab-treated SLE patients in three phase 3 belimumab clinical studies. Two highly correlated variants, rs293983 and rs364370, in the ANO3 (anoctamin 3) gene region were significantly associated with efficacy as measured by the SLE Response Index (SRI4) with a per-T-allele odds ratio (OR) of 2.15 [95% confidence interval (CI): 1.66-2.79, P=8.0×10]. In contrast, there was no association with SRI4 response in 577 placebo-treated patients (per-T-allele OR: 0.98; 95% CI: 0.74-1.29, P=0.87). A post-hoc analysis by geographic region revealed a strong SRI4 response signal in 157 belimumab-treated patients from Asia (per-T-allele OR=2.85, 95% CI: 1.41-5.74, P=0.0021). On the basis of this encouraging finding in Asian patients, we conducted a confirmatory analysis of the SRI4 end point in an independent phase 3 study of SLE patients from northeast Asia. We found no evidence of an association between rs293983 and SRI4 response in 204 belimumab-treated patients (per-T-allele OR: 0.90, 95% CI: 0.52-1.57, P=0.64). The inability to replicate the observed GWAS effect suggests this was a false positive result; hence, we failed to identify any genetic variants significantly associated with belimumab efficacy.
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Anoctaminas/genética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Inmunosupresores/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Administración Intravenosa , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/genética , Masculino , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Resultado del TratamientoRESUMEN
Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.
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Descubrimiento de Drogas , Farmacogenética , Biomarcadores Farmacológicos/análisis , Descubrimiento de Drogas/tendencias , Genotipo , Humanos , Farmacogenética/tendencias , Medicina de Precisión/tendencias , Resultado del TratamientoRESUMEN
OBJECTIVES: To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR). METHODS: DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR. RESULTS: The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants. CONCLUSION: The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.
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Fármacos Anti-VIH/efectos adversos , Didesoxinucleósidos/efectos adversos , Hipersensibilidad a las Drogas/genética , Infecciones por VIH/genética , Antígenos HLA-B/genética , Adulto , Fármacos Anti-VIH/uso terapéutico , Didesoxinucleósidos/uso terapéutico , Método Doble Ciego , Hipersensibilidad a las Drogas/etiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por VIH/tratamiento farmacológico , Humanos , Nevirapina/efectos adversos , Nevirapina/uso terapéutico , UgandaRESUMEN
The 2010 US FDA-Drug Industry Association (DIA) Pharmacogenomics (PGx) Workshop follows a series that began in 2002 bringing together multidisciplinary experts spanning regulatory authorities, medical research, healthcare and industry. This report summarizes the 'Building PGx into Labels' sessions from the workshop, which discussed the critical elements in developing PGx outcomes leading to product labels that inform efficacy and/or safety. Examples were drawn from US prescribing information, which integrated PGx knowledge into medical decisions (e.g., panitumumab, warfarin and clopidogrel). Attendees indicated the need for broader dialog and for guidelines on evidentiary considerations for PGx to be included into product labels. Also discussed was the understanding of appropriate PGx placement on labels; how to encourage adoption by medical communities of label recommendations on PGx tests; and, given the global nature of drug development, worldwide considerations including European Summary of Product Characteristics.
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Biomarcadores Farmacológicos/análisis , Diseño de Fármacos , Industria Farmacéutica , Etiquetado de Medicamentos/métodos , Programas de Gobierno , Farmacogenética/normas , Industria Farmacéutica/normas , Etiquetado de Medicamentos/legislación & jurisprudencia , Etiquetado de Medicamentos/tendencias , Farmacogenética/tendencias , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The 2010 US FDA-Drug Industry Association (DIA) Pharmacogenomics Workshop, the fifth in a series of meetings that begun in 2002, brought together multidisciplinary experts from regulatory authorities, medical research, healthcare and drug development. This article summarizes the 'Designing Pharmacogenomic Studies to be Fit for Purpose' track in which considerations regarding the use of retrospective and prospective studies were examined in relation to their ability to influence treatment decisions and labeling for drugs. The aim of the session, using real-world examples (KRAS/panitumumab and HLA-B*5701/abacavir), was to identify good scientific principles that would guide the design of studies to identify subgroups of responders during development programs (including marketed drugs), which could subsequently be used to guide treatment decisions.
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Biomarcadores Farmacológicos , Diseño de Fármacos , Industria Farmacéutica , Farmacogenética , Proyectos de Investigación , Biomarcadores Farmacológicos/análisis , Industria Farmacéutica/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Farmacogenética/normas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The objective of the ABC HSR pharmacogenetics program was to identify clinically useful genetic risk factors to predict an individual patient's risk for ABC HSR. The major histocompatibility complex allele, HLA-B*5701, was identified retrospectively and confirmed with independent sample sets. The clinical utility of prospective HLA-B*5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Important lessons from this pharmacogenetics program will be discussed in this paper.
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Didesoxinucleósidos/efectos adversos , Hipersensibilidad a las Drogas/genética , Inhibidores de la Transcriptasa Inversa/efectos adversos , Hipersensibilidad a las Drogas/mortalidad , Antígenos HLA-B/genética , Humanos , Fenotipo , Estudios Prospectivos , Proyectos de Investigación , Estudios RetrospectivosRESUMEN
Abacavir is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with abacavir develop a hypersensitivity reaction that requires discontinuation of the drug. In an initial pharmacogenetic study conducted in a predominantly White male population, multiple markers in the human leukocyte antigen (HLA)-B chromosomal region were associated with hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x 10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78, p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients at risk for hypersensitivity to abacavir across diverse patient populations. Efforts are ongoing to identify markers with sufficient sensitivity and specificity to be clinically useful. Even after a marker set is identified, appropriate clinical identification and management of hypersensitivity to abacavir must remain the cornerstone of clinical practice.
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Fármacos Anti-VIH/efectos adversos , Didesoxinucleósidos/efectos adversos , Hipersensibilidad a las Drogas/etiología , Variación Genética , Antígenos HLA-B/genética , Población Negra/genética , Estudios de Casos y Controles , Hipersensibilidad a las Drogas/metabolismo , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Factor de Necrosis Tumoral alfa/genética , Población Blanca/genéticaRESUMEN
Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.