RESUMO
BACKGROUND: Letrozole, an aromatase inhibitor metabolised via CYP2A6 and CYP3A4/5 enzymes, is used as adjuvant therapy for women with hormone receptor (HR)-positive early breast cancer. The objective of this study was to quantify the impact of CYP2A6 genotype on letrozole pharmacokinetics (PK), to identify non-adherent patients using a population approach and explore the possibility of a relationship between non-adherence and early relapse. METHODS: Breast cancer patients enrolled in the prospective PHACS study (ClinicalTrials.gov NCT01127295) and treated with adjuvant letrozole 2.5 mg/day were included. Trough letrozole concentrations (Css,trough) were measured every 6 months for 3 years by a validated LC-MS/MS method. Concentration-time data were analysed using non-linear mixed effects modelling. Three methods were evaluated for identification of non-adherent subjects using the base PK model. RESULTS: 617 patients contributing 2534 plasma concentrations were included and led to a one-compartment PK model with linear absorption and elimination. Model-based methods identified 28 % of patients as non-adherent based on high fluctuations of their Css,trough compared to 3 % based on patient declarations. The covariate analysis performed in adherent subjects revealed that CYP2A6 intermediate (IM) and slow metabolisers (SM) had 21 % (CI95 % = 12 - 30 %) and 46 % (CI95 % = 41 - 51 %) lower apparent clearance, respectively, compared to normal and ultrarapid metabolisers (NM+UM). Early relapse (19 patients) was not associated with model-estimated, concentration-based or declared adherence in the total population (p = 0.41, p = 0.37 and p = 0.45, respectively). CONCLUSIONS: These findings will help future investigations focusing on the exposure-efficacy relationship for letrozole in adjuvant setting.
Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Letrozol , Adesão à Medicação , Humanos , Letrozol/farmacocinética , Letrozol/administração & dosagem , Letrozol/uso terapêutico , Letrozol/sangue , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Pessoa de Meia-Idade , Idoso , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/sangue , Adulto , Quimioterapia Adjuvante/métodos , Modelos Biológicos , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 µL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.
Assuntos
Inibidores da Aromatase , Letrozol , Nitrilas , Espectrometria de Massas em Tandem , Triazóis , Animais , Letrozol/sangue , Letrozol/farmacocinética , Letrozol/química , Camundongos , Espectrometria de Massas em Tandem/métodos , Inibidores da Aromatase/sangue , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/química , Cromatografia Líquida de Alta Pressão/métodos , Nitrilas/sangue , Nitrilas/farmacocinética , Triazóis/sangue , Triazóis/farmacocinética , Triazóis/química , Reprodutibilidade dos Testes , Modelos Lineares , Limite de Detecção , Feminino , MasculinoRESUMO
ABSTRACT Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.
Assuntos
Humanos , Masculino , Feminino , Triazóis/farmacocinética , Estatura/efeitos dos fármacos , Inibidores da Aromatase/farmacocinética , Nitrilas/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores da Aromatase/uso terapêutico , Interações Medicamentosas , Letrozol , AnastrozolRESUMO
Summary Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.
Resumo Os inibidores de aromatase têm emergido como uma endocrinoterapia alternativa para o tratamento de câncer de mama sensível a hormônios em mulheres pós-menopáusicas. A utilização de inibidores de terceira geração, representados por exemestano, letrozol e anastrozol, é atualmente indicada. Anastrozol é um composto não esteroide e um inibidor potente e seletivo da enzima aromatase. Embora alguns estudos tenham demonstrado que as suas propriedades farmacodinâmicas e farmacocinéticas podem ser afetadas pela variabilidade interindividual, esse fármaco tem sido recentemente utilizado em todas as configurações de tratamento do câncer de mama. Na doença metastática, é atualmente considerado o tratamento de primeira linha em mulheres pós-menopáusicas com tumores de mama e receptor de estrogênio positivo. O anastrozol tem mostrado resultados promissores no tratamento adjuvante do câncer de mama em estágio inicial em mulheres na pós-menopausa. Ele também conseguiu resultados interessantes na quimioprevenção da doença. Portanto, em virtude da importância do anastrozol tanto no tratamento endócrino quanto na quimioprevenção do câncer de mama hormoniossensível em mulheres na pós-menopausa, propusemos a atual revisão da literatura na base de dados SciELO e PubMed de artigos publicados nos últimos 10 anos.
Assuntos
Humanos , Feminino , Triazóis/uso terapêutico , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Quimioprevenção/métodos , Inibidores da Aromatase/uso terapêutico , Nitrilas/uso terapêutico , Tamoxifeno/uso terapêutico , Tamoxifeno/farmacocinética , Triazóis/farmacocinética , Reprodutibilidade dos Testes , Resultado do Tratamento , Quimioterapia Adjuvante , Pós-Menopausa , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacocinética , Inibidores da Aromatase/farmacocinética , Anastrozol , Nitrilas/farmacocinéticaRESUMO
Objetivos: El objetivo del estudio fue analizar los cambios en la densidad mineral ósea (DMO) a lo largo del tratamiento con inhibidores de aromatasa (IA) en la práctica clínica y evaluar la asociación entre el gen CYP11A1 y la variación de DMO al final del tratamiento. Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama, en tratamiento con IA. Se analizó la variación de DMO durante todo el tratamiento con IA, así como las diferencias entre las pacientes tratadas y no-tratadas previamente con tamoxifeno (TMX). Tres polimorfismos (rs4077581, rs11632698 y rs900798) del gen CYP11A1, fueron genotipados para su asociación con la variación de DMO. Resultados: Las pacientes tratadas con TMX mostraron pérdidas más aceleradas de DMO que las no tratadas previamente con TMX (60% menos en columna y 46% en fémur a los 2 años y 70% menos en columna y 63% en fémur a los 3 años). No obstante, al final del tratamiento no se detectaron diferencias significativas en la pérdida de DMO entre ambos grupos de pacientes. Los 3 polimorfismos del gen CYP11A1 resultaron significativamente asociados a la variación de DMO en fémur al final del tratamiento. Conclusiones: La DMO disminuyó de forma más acelerada en las pacientes con tratamiento previo con TMX que en las que solo recibieron AI, a pesar de que no se detectaron diferencias significativas al final de tratamiento. Polimorfismos en el gen CYP11A1 están relacionados con la variación de la DMO en respuesta al tratamiento con IA (AU)
Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment. Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation. Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment. Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment (AU)
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Densidade Óssea , Inibidores da Aromatase/farmacocinética , Neoplasias da Mama/complicações , Estudos Prospectivos , Tamoxifeno/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
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We aimed to investigate the effects of the aromatase inhibitor letrozole on femur fracture and serum levels of alkaline phosphatase (ALP), calcium and phosphate in female rats. Intact 32 Sprague-Dawley female rats were divided into four groups (n=8): control, letrozole 0.2 , letrozole 1 (treatment of 0.2 and 1 mg/kg for six weeks) and recovery (letrozole-treated 1 mg/kg for six weeks then allowed to recover for two weeks). Besides, 24 ovariectomized rats were divided into three groups (n=8): ovariectomized+control, ovariectomized+letrozole and ovariectomized+letrozole+ estradiol (10 ìg/rat). After experimental period, rats femur bones were removed for biomechanical studies following decapitation. Serum ALP, calcium and phosphate were measured. Biomechanical values, ALP and phosphate significantly increased by letrozole in a dose-dependent manner (p<0.05) while calcium levels and net bone area decreased (p<0.05). Ultimate strength was positively correlated with ALP and phosphate and negatively correlated with calcium. The results indicate that letrozole may increase risk of bone fracture and affect bone biomarkers such as ALP, calcium and phosphate in both intact and ovariectomized rats (AU)