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1.
Lung Cancer ; 160: 44-49, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34403911

RESUMO

BACKGROUND: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). METHODS: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. RESULTS: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. CONCLUSIONS: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Taxoides/uso terapêutico
2.
Clin Pharmacokinet ; 60(1): 69-77, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32557346

RESUMO

INTRODUCTION: Erlotinib's gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow's milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison. METHOD: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days. RESULTS: Erlotinib area under the curve from time zero to 24 h (AUC24) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; - 3%; 95% confidence interval [CI] - 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI - 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC24 by 47% (n = 9; 95% CI - 57 to - 34%; p < 0.001) and Cmax by 56% (95% CI - 64 to - 46%; p < 0.001). No differences in toxicities were observed between milk and water. CONCLUSION: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC24 and Cmax and should be avoided if possible.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Cloridrato de Erlotinib , Esomeprazol , Neoplasias Pulmonares , Leite/metabolismo , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos Cross-Over , Interações Medicamentosas , Cloridrato de Erlotinib/farmacologia , Esomeprazol/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/farmacologia
3.
J Pharm Biomed Anal ; 172: 175-182, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31051406

RESUMO

An LC-MS/MS method was developed and validated to quantify the tyrosine kinase inhibitor erlotinib in human scalp hair, as alternative matrix to monitor long-term erlotinib exposure. Hair samples from 10 lung cancer patients were measured and correlated with plasma concentrations. Hair segments of 1 ± 0.1 cm each were pulverized and for at least 18 h incubated in methanol at ambient temperature. A liquid-liquid extraction purified the extracts and they were analyzed with LC-MS/MS, using erlotinib-d6 as internal standard. The procedure method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity and accuracy. The within and between run precisions including the lower limit of quantification did not exceed 12.5%, while the accuracy ranged from 103 to 106%. A weak correlation between hair and plasma concentration was found (R2 = 0.48). Furthermore, a large inter-individual variability was noted in the disposition of both plasma and hair samples. The highest hair concentrations were observed in black hair compared with other (grey and brown) hair colors. Generally, a linear reduction in hair concentration was found from proximal to distal hair segments. Additional in vitro experiments suggest an accelerated degradation of erlotinib in hair by artificial UV light and also wash-out by shampoo mixtures pretreatment compared with control samples. In conclusion, a reliable and robust LC-MS/MS method was developed to quantify erlotinib in hair. However, clinical and in vitro evaluations showed that the method is not suitable for monitoring long-term erlotinib exposure. The pitfalls of this application outweigh the current benefits.


Assuntos
Monitoramento de Medicamentos/métodos , Cloridrato de Erlotinib/análise , Cabelo/química , Inibidores de Proteínas Quinases/análise , Variação Biológica da População/efeitos dos fármacos , Variação Biológica da População/efeitos da radiação , Cromatografia Líquida de Alta Pressão , Cosméticos/farmacologia , Estabilidade de Medicamentos , Cabelo/efeitos dos fármacos , Cabelo/efeitos da radiação , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Couro Cabeludo , Espectrometria de Massas em Tandem , Fatores de Tempo , Raios Ultravioleta
4.
Acta Oncol ; 58(2): 237-242, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30451552

RESUMO

BACKGROUND/PURPOSE: To investigate prognostic factors for death within 6 months of stereotactic body radiotherapy (SBRT) for patients with peripheral early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 586 NSCLC patients with peripheral tumors treated with SBRT. Potential patient and tumor prognostic factors, including the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS), were analyzed by logistic regression analysis for association with early mortality (death <6 months after SBRT). Additionally, CCI and CIRS were compared with respect to their predictive ability for early mortality by comparing multivariate models with each comorbidity index, and assessing their respective discriminatory abilities (C-index). RESULTS: A total of 36 patients (6.1%) died within 6 months of the start of SBRT. With a median follow-up of 25 months, 3-year overall survival was 54%. CIRS and tumor diameter were significant predictors of early mortality on multivariate analysis (p = .001). Patients with a CIRS score of 8 or higher and a tumor diameter over 3 cm had a 6-month survival of 70% versus 97% for those lacking these two features (p < .001). CCI was not predictive for early mortality on univariate nor multivariate analysis; the model containing CCI had a C-index of 0.65 versus 0.70 for the model containing CIRS. CONCLUSION: CIRS and tumor diameter predict for early-mortality in peripheral early-stage NSCLC treated with SBRT. CIRS may be a more useful comorbidity index than CCI in this population when assessing short-term life expectancy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Radiocirurgia/métodos , Estudos Retrospectivos , Análise de Sobrevida , Sobrevivência , Fatores de Tempo
5.
Clin Pharmacokinet ; 56(7): 683-688, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28101705

RESUMO

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Bomba de Prótons/uso terapêutico , Administração Oral , Interações Medicamentosas , Humanos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores da Bomba de Prótons/farmacologia
6.
J Clin Oncol ; 34(12): 1309-14, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-26858332

RESUMO

PURPOSE: Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. PATIENTS AND METHODS: In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. RESULTS: Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. CONCLUSION: Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib.


Assuntos
Antineoplásicos/farmacocinética , Bebidas Gaseificadas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/farmacocinética , Interações Alimento-Droga , Absorção Gastrointestinal , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Cross-Over , Monitoramento de Medicamentos , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/sangue , Esomeprazol/administração & dosagem , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores da Bomba de Prótons/administração & dosagem
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