RESUMO
Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.
Assuntos
Síndrome Coronariana Aguda , Arildialquilfosfatase/genética , Mutação de Sentido Incorreto , Cloridrato de Prasugrel , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/terapia , Idoso , Substituição de Aminoácidos , Arildialquilfosfatase/metabolismo , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinéticaRESUMO
BACKGROUND: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. METHODS: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. RESULTS: In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02). CONCLUSIONS: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Assuntos
Síndrome Coronariana Aguda/terapia , Hidrocarboneto de Aril Hidroxilases/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético , Ticlopidina/análogos & derivados , Adulto , Angioplastia Coronária com Balão , Área Sob a Curva , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Clopidogrel , Terapia Combinada , Citocromo P-450 CYP2C19 , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Stents , Trombose/epidemiologia , Trombose/genética , Ticlopidina/efeitos adversos , Ticlopidina/metabolismo , Ticlopidina/farmacologia , Ticlopidina/uso terapêuticoRESUMO
AIMS: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. METHODS: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. RESULTS: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). CONCLUSIONS: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Piperazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Tiofenos/farmacologia , Ticlopidina/análogos & derivados , Adulto , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Linhagem , Piperazinas/farmacocinética , Agregação Plaquetária/genética , Inibidores da Agregação Plaquetária/farmacocinética , Polimorfismo Genético/genética , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Tiofenos/farmacocinética , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Adulto JovemRESUMO
BACKGROUND: Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435CâT, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. METHODS: We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435CâT and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435CâT genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. FINDINGS: In patients treated with clopidogrel, ABCB1 3435CâT genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435CâT and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. INTERPRETATION: Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. FUNDING: Daiichi Sankyo Company Ltd and Eli Lilly and Company.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Angioplastia Coronária com Balão , Hidrocarboneto de Aril Hidroxilases/genética , Variação Genética , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP , Doenças Cardiovasculares/etiologia , Clopidogrel , Citocromo P-450 CYP2C19 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Piperazinas/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Polimorfismo de Nucleotídeo Único , Cloridrato de Prasugrel , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiofenos/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêuticoRESUMO
The thienopyridine, clopidogrel bisulfate (clopidogrel), is the most widely prescribed antiplatelet therapy in the world. Clopidogrel, alone or in conjunction with aspirin as part of a dual antiplatelet therapy regimen, is the standard of care for reducing ischemic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke, or established peripheral artery disease. Initially approved for use in 1997, the label was updated by both the USA Food and Drug Administration and the European Medicines Agency in 2009 to include information regarding cytochrome P450 (CYP) genotype status and concomitant proton pump inhibitor use. Labeling warns of reduced effectiveness in those with impaired CYP2C19 function and to avoid concomitant clopidogrel use with drugs that are strong or moderate CYP2C19 inhibitors, such as omeprazole. The interpretation of this warning and the implementation in clinical practice is not without controversy. The following review provides a summary of the published evidence regarding CYP2C19 function, both genotype status and drug inhibition from concomitant proton pump inhibitors use, and response to clopidogrel.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Inibidores da Agregação Plaquetária/metabolismo , Ticlopidina/análogos & derivados , Alelos , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/fisiologia , Clopidogrel , Citocromo P-450 CYP2C19 , Interações Medicamentosas , Humanos , Farmacogenética , Polimorfismo Genético , Ticlopidina/metabolismoRESUMO
BACKGROUND: Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. METHODS AND RESULTS: The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. CONCLUSIONS: Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Pró-Fármacos/farmacocinética , Tiofenos/farmacocinética , Adulto , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Biotransformação/genética , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Citocromo P-450 CYP2C19 , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Genótipo , Humanos , Masculino , Microssomos Hepáticos/enzimologia , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético , Cloridrato de Prasugrel , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2Y12 , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel. METHODS: In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. FINDINGS: In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20). INTERPRETATION: The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. FUNDING: Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.
Assuntos
Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Clopidogrel , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Piperazinas/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel , Modelos de Riscos Proporcionais , Inibidores da Bomba de Prótons/efeitos adversos , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tiofenos/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
AIMS: The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. METHODS AND RESULTS: Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. CONCLUSION: Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Aspirina/uso terapêutico , Doença das Coronárias/metabolismo , Piperazinas/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Tiofenos/metabolismo , Ticlopidina/análogos & derivados , Clopidogrel , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Citocromo P-450 CYP2C19 , Interações Medicamentosas , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacocinética , Cloridrato de Prasugrel , Tiofenos/farmacocinética , Tiofenos/uso terapêutico , Ticlopidina/metabolismo , Ticlopidina/farmacocinética , Ticlopidina/uso terapêuticoRESUMO
Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines.
Assuntos
Farmacogenética , Inibidores da Agregação Plaquetária/farmacologia , Tienopiridinas/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Marcadores Genéticos , Humanos , Inibidores da Agregação Plaquetária/metabolismo , Medicina de Precisão/métodos , Pró-Fármacos , Tienopiridinas/metabolismoRESUMO
Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.
Assuntos
Síndrome Coronariana Aguda/terapia , Angioplastia Coronária com Balão/efeitos adversos , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/mortalidade , Angioplastia Coronária com Balão/mortalidade , Interações Medicamentosas , Resistência a Medicamentos , Medicina Baseada em Evidências , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Trombose/etiologia , Trombose/mortalidade , Trombose/prevenção & controle , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Biomarcadores Farmacológicos/análise , Desenho de Fármacos , Indústria Farmacêutica , Rotulagem de Medicamentos/métodos , Programas Governamentais , Farmacogenética/normas , Indústria Farmacêutica/normas , Rotulagem de Medicamentos/legislação & jurisprudência , Rotulagem de Medicamentos/tendências , Farmacogenética/tendências , Estados Unidos , United States Food and Drug AdministrationRESUMO
Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.5-1.8 mg/kg per day) were genotyped on CYP2D6, which metabolizes atomoxetine, and 108 single nucleotide polymorphisms in the NET/SLC6A2 gene. Response was defined as a minimum decrease of 25% in ADHD Rating Scale IV-Parent Version and a Clinical Global Impression-Severity (CGI-S) score less than or equal to 2 at week 6. Interindividual response was independent of the genetic variants of CYP2D6. Significant (p<0.05) associations between 20 NET/SLC6A2 single nucleotide polymorphisms (SNPs) and clinical efficacy in atomoxetine responders, compared with non-responders, were observed. The genomic region across exons 4 to 9 of NET/SLC6A2, where 36 SNPs have been genotyped, was associated with treatment response in both cohorts (p<0.01, odds ratio=2.2 and p=0.026, odds ratio=6.3, respectively), in the combined cohort (p<0.01, odds ratio=1.83), and in the subgroup of Caucasians only (p=0.02, odds ratio=1.8). Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter. Taking into account the high heritability of ADHD, the significance of the present finding and replication of a similar haplotype allele sequence result in an independent cohort, it is suggested that further assessment of this region could be useful in determining response to atomoxetine in ADHD.