RESUMO
Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.
Assuntos
Preparações Farmacêuticas/administração & dosagem , Farmacogenética/métodos , Medicina de Precisão/métodos , Criança , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Preparações Farmacêuticas/metabolismoRESUMO
Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
Assuntos
Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Polimorfismo de Nucleotídeo Único/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Criança , Estudos Transversais/métodos , Humanos , Quimioterapia de Manutenção/métodos , Estudos Observacionais como Assunto/métodosRESUMO
Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, ß = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
Assuntos
Creatinina/sangue , Estudo de Associação Genômica Ampla/métodos , Vancomicina/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Cromossomos Humanos/genética , Cromossomos Humanos Par 6/genética , Conexina 43/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
AIM: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. MATERIALS & METHODS: Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. RESULTS: CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). CONCLUSION: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.
Assuntos
Citocromo P-450 CYP2C9/genética , Sistema Enzimático do Citocromo P-450/genética , Hemorragia/genética , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Adulto , Idoso , Bancos de Espécimes Biológicos , Família 4 do Citocromo P450 , Relação Dose-Resposta a Droga , Etnicidade , Feminino , Frequência do Gene , Estudos de Associação Genética , Variação Genética , Genótipo , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Varfarina/administração & dosagemRESUMO
The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P < 0·0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (P = 0·001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.
Assuntos
Anticoagulantes/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Variação Genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adolescente , Fatores Etários , Alelos , Criança , Pré-Escolar , Estudos Transversais , Citocromo P-450 CYP2C9 , Genótipo , Humanos , Lactente , Farmacogenética , Estudos RetrospectivosRESUMO
Warfarin is the most commonly used oral anticoagulant worldwide. Warfarin has a narrow therapeutic index, requiring frequent monitoring of the INR to achieve therapeutic anticoagulation. The role of pharmacogenomics in warfarin disposition and response has been well established in adults, but remains unclear for pediatric patients. In this review, we focus on the important CYP2C9 and VKORC1 variants involved in warfarin response, our current understanding of warfarin disposition and pharmacogenomics, and recent warfarin pharmacogenetic studies in pediatric patients. Finally, we discuss the need for future pediatric studies and the clinical implications of developing pharmacogenetic-based dosing algorithms in children.
