RESUMO
The workshop on "New Approaches to Investigate Drug-Induced Hypersensitivity" was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development. This perspective reviews the clinical and immunological bases of drug hypersensitivity and summarizes various experts' views on the different topics covered during the meeting.
Assuntos
Hipersensibilidade a Drogas , Animais , Bioensaio , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/imunologia , Indústria Farmacêutica , Predisposição Genética para Doença , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Fenótipo , Fatores de RiscoRESUMO
It is hypothesized that lapatinib-induced liver injury is caused by HLA-mediated antigen presentation to CD4 positive T cells. However, analysis of PBMC and cloned T-cells from patients with HLA-DRB1*07:01-restricted lapatinib-induced liver injury revealed no evidence for drug-specific activation. T cells were exposed to lapatinib, the M11 aldehyde, and quinone imine [oxidized form of hydroquinone amine M1] metabolites. Reactivity of the quinone imine was confirmed by mass spectrometry.
Assuntos
Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Cadeias HLA-DRB1/genética , Ativação Linfocitária/efeitos dos fármacos , Quinazolinas/efeitos adversos , Linfócitos T/efeitos dos fármacos , Antineoplásicos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Humanos , Lapatinib , Quinazolinas/farmacologiaRESUMO
We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.
Assuntos
Teorema de Bayes , Predisposição Genética para Doença , Modelos Logísticos , Neoplasias da Próstata/genética , Idoso , Algoritmos , Área Sob a Curva , Calibragem , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , População Branca/genéticaRESUMO
PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.
Assuntos
Alanina Transaminase/metabolismo , Bilirrubina/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Oncologia/estatística & dados numéricos , Modelos Estatísticos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Testes de Função Hepática , Análise Multivariada , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.
Assuntos
Alanina Transaminase/sangue , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/enzimologia , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/enzimologia , Proteínas de Membrana/genética , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/genética , Feminino , Genes MHC Classe I , Genes MHC da Classe II , Marcadores Genéticos , Proteína da Hemocromatose , Humanos , Indazóis , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIM: Pyrexia is a common adverse event (AE) on dabrafenib treatment (monotherapy or combination with trametinib). Since germline SNPs and HLA alleles are implicated in drug-induced AEs, this study investigated their association with pyrexia. PATIENTS & METHODS: 1006 melanoma subjects from five dabrafenib-trametinib clinical studies underwent genotyping for genome-wide SNPs, which enabled imputation of 150 HLA alleles. SNP/HLA allele frequencies were compared between pyrexia cases (n = 218) and controls (n = 361) out of the 1006 subjects by meta-analysis. RESULTS: This analysis had adequate power to detect association of common SNPs or HLA alleles with moderate to large effects on pyrexia (odds ratio >6), but no significant association was found. CONCLUSION: The study suggests that common genetic variation or HLA polymorphisms do not contribute substantially to dabrafenib-induced pyrexia.
Assuntos
Antineoplásicos/efeitos adversos , Febre/induzido quimicamente , Antígenos HLA/genética , Imidazóis/efeitos adversos , Melanoma/tratamento farmacológico , Oximas/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos de Casos e Controles , Febre/genética , Estudos de Associação Genética , Humanos , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
PURPOSE: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury. EXPERIMENTAL DESIGN: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted. RESULTS: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation. CONCLUSIONS: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.
Assuntos
Alelos , Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Predisposição Genética para Doença , Antígenos HLA-B/genética , Neoplasias/complicações , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Feminino , Antígenos HLA-B/química , Heterozigoto , Humanos , Indazóis , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Adulto JovemRESUMO
Rash is a common side effect of lapatinib treatment. Since human leukocyte antigen (HLA) alleles have been implicated in multiple drug-induced cutaneous reactions, this study investigated the association of HLA alleles with lapatinib-induced rash. 1191 participants from a large lapatinib monotherapy trial underwent HLA genotyping, and allele carriage frequencies between rash cases and controls were compared. This analysis had adequate power to detect an association of common HLA alleles with rash, similar to those reported previously. No HLA alleles were significantly associated with lapatinib-induced rash, including the previously identified lapatinib hepatotoxicity biomarker HLA-DRB1*07:01 (p = 0.87). The present study is consistent with the view that lapatinib-induced rash is not the consequence of HLA-restricted, immune-mediated mechanisms.
Assuntos
Antineoplásicos/efeitos adversos , Toxidermias/genética , Antígenos HLA/genética , Quinazolinas/efeitos adversos , Alelos , Antineoplásicos/uso terapêutico , DNA/genética , Toxidermias/imunologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Lapatinib , Polimorfismo Genético/genética , Quinazolinas/uso terapêuticoRESUMO
PURPOSE: Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2-positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). PATIENTS AND METHODS: The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. RESULTS: In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. CONCLUSION: These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cadeias HLA-DRB1/genética , Quinazolinas/efeitos adversos , Adulto , Idoso , Alelos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/imunologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Cadeias HLA-DRB1/imunologia , Humanos , Lapatinib , Pessoa de Meia-Idade , Estudos Prospectivos , Quinazolinas/uso terapêutico , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Tyrosine kinase inhibitors (TKIs) represent important therapeutic alternatives to, or combinations with, traditional cytotoxic chemotherapy. Despite their selective molecular targeting and demonstrated clinical benefit, TKIs produce a range of serious adverse events, including drug-induced liver injury, that require careful patient management to maintain treatment benefit without harm. Genetic characterization of serious adverse events can identify mechanisms of injury and improve safety risk management. This review presents pharmacogenetic comparisons of two approved TKIs, lapatinib and pazopanib, which reveal different mechanisms of injury and inform the characteristics and risk of serious liver injury in treated patients. The data presented demonstrate the utility of genetic studies to investigate drug-induced liver injury and potentially support its management in patients.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Glucuronosiltransferase/genética , Inibidores de Proteínas Quinases/toxicidade , Biomarcadores Farmacológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Doença de Gilbert/tratamento farmacológico , Doença de Gilbert/genética , Humanos , Indazóis , Lapatinib , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/toxicidade , Quinazolinas/administração & dosagem , Quinazolinas/toxicidade , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidadeRESUMO
BACKGROUND: Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk. OBJECTIVE: To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa. DESIGN, SETTING, AND PARTICIPANTS: Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers. RESULTS AND LIMITATIONS: Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10(-8)). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p<0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p=0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ≥ 7) PCa. A major limitation of this study was its focus on white patients only. CONCLUSIONS: Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study.
Assuntos
Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Biópsia , Reações Falso-Negativas , Marcadores Genéticos , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco/métodosRESUMO
PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs. PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients. RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively. CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Hepatopatias/etiologia , Quinazolinas/efeitos adversos , Idoso , Alanina Transaminase/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Cadeias alfa de HLA-DQ , Humanos , Lapatinib , Fígado/efeitos dos fármacos , Testes de Função Hepática , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
PURPOSE: Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. PATIENTS AND METHODS: Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. RESULTS: Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%). CONCLUSION: Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Proteínas de Neoplasias/genética , Neovascularização Fisiológica/genética , Polimorfismo de Nucleotídeo Único , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Estudos Cross-Over , Análise Mutacional de DNA , Intervalo Livre de Doença , Marcadores Genéticos , Genótipo , Mutação em Linhagem Germinativa , Humanos , Indazóis , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Modelos de Riscos Proporcionais , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Sulfonamidas/farmacologiaRESUMO
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are highly effective in the treatment of type 2 diabetes. In some patients, PPARgamma ligands are associated with fluid retention/oedema, for which the mechanism is not fully understood. A pharmacogenetic study was undertaken to investigate effects of variations in 21 candidate genes related to epithelial sodium channel (ENaC) pathways on oedema. This study used DNA samples collected from type 2 diabetes phase III clinical trials of the PPARgamma agonist farglitazar (administered alone or in combination with insulin or glyburide) and investigated oedema reported as an adverse event as phenotype. Initial case-control analysis of oedema identified candidate gene single nucleotide polymorphisms with significant associations. These included three polymorphisms in ENaCbeta subunit (SCNN1B) that showed significant associations (P<0.05) with the two combination treatments in discrete regions of the gene, but not farglitazar treatment alone. Sequencing of SCNN1B in 207 Caucasian participants receiving farglitazar plus insulin or glyburide combination therapies, identified additional polymorphisms that were also significantly associated with oedema (P<0.0005) and maintained the treatment-regional associations. Further covariate analysis accounting for clinical factors influencing oedema supported these observations. One of the SCNN1B polymorphisms, at position -405 of the 5' flanking region (rs34241435), was predicted to modify transcriptional interactions and in a transfected COS cell luciferase reporter gene assay exhibited higher promoter activity. These exploratory studies provide clinical pharmacogenetic and functional genomic evidence to support a pivotal role for ENaC regulation in PPARgamma-induced oedema and provide insight into mechanisms and possible management of this side effect.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Edema/etiologia , Canais Epiteliais de Sódio/genética , Oxazóis/efeitos adversos , Tirosina/análogos & derivados , Adulto , Idoso , Sequência de Bases , Primers do DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Edema/metabolismo , Feminino , Genes Reporter , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , Farmacogenética , Fenótipo , Regiões Promotoras Genéticas , Fatores de Risco , Fatores de Tempo , Tirosina/efeitos adversosRESUMO
BACKGROUND: GW320659, a highly selective neuronal norepinephrine and dopamine re-uptake inhibitor, has been evaluated for the treatment of obesity. Scrutiny of the weight loss data from a phase II study (GlaxoSmithKline study OBS20001) showed a wide variation in weight loss response following GW320659 treatment and the possibility that the study population might include subgroups with enhanced weight loss response. METHODS: Pharmacogenetic analysis was performed in 191 subjects prospectively ascertained from a Phase II dose ranging study to evaluate the influence of genotype on weight loss efficacy and safety of GW320659 in obese subjects. RESULTS: Common genetic polymorphisms in the drug target (norepinephrine transporter protein 1, SLC6A2) and mechanism pathway (NMDA receptor channel NR1 subunit, GRIN1) were associated with increased weight loss following GW320659 treatment in a proportion (36%) of the study population. In the patient subgroup selected for these genotypes, GW320659 (15 mg/day) produced a significant difference in mean weight loss of 7.84 kg (SD 5.23, n = 14), compared to 2.53 kg (SD 5.17, n = 24) in the subgroup that did not possess the genotypes (P = 0.006). This subgroup also showed a highly significant weight loss response for GW320659 compared to placebo (+0.31 kg, SD 3.32, n = 16) with the same genotypes (P < 0.0001). In addition, there was no difference in placebo response between either subgroup. CONCLUSIONS: Polymorphisms in SLC6A2 and GRIN1 could be used to maximize effective obesity pharmacotherapy by norepinephrine/dopamine transporter inhibitors by identifying patients that may be predisposed to particularly good treatment weight loss response.