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1.
Ann Oncol ; 31(3): 412-421, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32067683

RESUMO

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.


Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias das Glândulas Salivares , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Terapia de Alvo Molecular , Receptor ErbB-2/genética , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/genética , Glândulas Salivares , Trastuzumab
2.
Antimicrob Agents Chemother ; 57(12): 6097-105, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24080649

RESUMO

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.


Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/farmacocinética , Polietilenoglicóis/farmacocinética , Insuficiência Renal/tratamento farmacológico , Ribavirina/farmacocinética , Adulto , Idoso , Antivirais/sangue , Antivirais/farmacologia , Área Sob a Curva , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/sangue , Interferon-alfa/farmacologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Insuficiência Renal/sangue , Insuficiência Renal/complicações , Insuficiência Renal/virologia , Ribavirina/sangue , Ribavirina/farmacologia , Índice de Gravidade de Doença
3.
Eur J Clin Pharmacol ; 69(10): 1777-84, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23765407

RESUMO

PURPOSE: Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders. METHODS: Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference). RESULTS: The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively. CONCLUSIONS: The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Hepatite C Crônica/enzimologia , Midazolam/análogos & derivados , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Feminino , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Análise dos Mínimos Quadrados , Masculino , Taxa de Depuração Metabólica , Midazolam/sangue , Midazolam/farmacocinética , Pessoa de Meia-Idade , Adulto Jovem
4.
Aliment Pharmacol Ther ; 35(10): 1209-20, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22469033

RESUMO

BACKGROUND: Amongst Caucasian, Hispanic and African Americans with genotype 1 hepatitis C virus (HCV), there is a wide variation in response to treatment with peginterferon alfa-2a (PEG-IFN alfa-2a) and ribavirin. AIM: To evaluate the pharmacokinetics (PK) of PEG-IFN alfa-2a and ribavirin among these three groups. METHODS: Forty-seven patients with genotype 1 CHC (17 African Americans, 14 Hispanics and 16 Caucasians) received 8 weeks of PEG-IFN alfa-2a (180 µg/week) and ribavirin (1000 or 1200 mg/day). PEG-IFN alfa-2a serum concentrations and ribavirin plasma concentrations were measured following the first dose and at week 8. Pharmacokinetic parameters (C(max), T(max), AUC, CL/F) were estimated using noncompartmental methods. RESULTS: There was no difference in the pharmacokinetic parameters for PEG-IFN alfa-2a following single-dose or steady-state administration between African American or Hispanic patients compared with Caucasian patients. Ribavirin pharmacokinetic parameters were similar between Hispanic and Caucasian patients for single-dose and steady-state administration. The single-dose C(max) was 33% lower (P < 0.05) in African American compared with Caucasian patients. Other ribavirin single-dose and steady-state pharmacokinetic parameters were slightly decreased (approximately 20% lower) in African American patients, but were not considered clinically meaningful. CONCLUSIONS: No differences were observed in PEG-IFN alfa-2a pharmacokinetic parameters between African American or Hispanic patients compared with Caucasian patients. For ribavirin, no differences were observed in pharmacokinetic parameters between Hispanic and Caucasian patients. While a trend towards increased ribavirin clearance and decreased exposure was observed in African American patients vs. Caucasian patients, the differences were small and not considered clinically meaningful (Clinical Trial Number: NP17354).


Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/metabolismo , Interferon-alfa/farmacocinética , Polietilenoglicóis/farmacocinética , Ribavirina/farmacocinética , Adulto , Negro ou Afro-Americano/genética , Antivirais/administração & dosagem , Área Sob a Curva , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Genótipo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Hispânico ou Latino/genética , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Ribavirina/administração & dosagem , População Branca/genética
5.
J Nutr ; 131(6): 1694-9, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11385055

RESUMO

Orlistat is a gastrointestinal lipase inhibitor that is used to reduce dietary fat absorption and to enhance weight loss in subjects consuming a hypocaloric diet. To assess whether orlistat has an effect on the metabolism of six minerals, a 21-d, double-blind, randomized, parallel-group, placebo-controlled mineral balance study was conducted in obese (body mass index > 30 kg/m(2)) men. Subjects consumed a hypocaloric diet with a constant daily mineral content and received daily oral treatment with orlistat (120 mg three times daily) (n = 14) or placebo (three times daily) (n = 14) for 21 d. After a 14-d equilibration period, calcium, phosphorus, magnesium, iron, copper and zinc balances were assessed for d 15-21. In addition, the effect of diet and orlistat treatment on bone metabolism was estimated from measurement of biomarkers of bone formation and bone resorption. Serum and urine electrolytes were also measured at baseline and at the end of treatment. Orlistat inhibited fat absorption by approximately 33% (P < 0.05). There were no significant differences in mineral apparent absorption, urinary mineral loss or mineral balance between the orlistat and placebo groups. Markers of bone turnover and serum and urine electrolytes did not differ between the orlistat and placebo groups. Orlistat was well tolerated; adverse events were of mild or moderate intensity, and the majority of these events were unrelated or remotely related to study treatment. In obese men consuming a hypocaloric diet, the administration of orlistat had no significant effect on the balance of six selected minerals. In addition, biomarkers of bone turnover, as well as serum and urine electrolytes, were not affected by orlistat treatment.


Assuntos
Fármacos Antiobesidade/farmacologia , Osso e Ossos/metabolismo , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Minerais/metabolismo , Obesidade/metabolismo , Adulto , Fármacos Antiobesidade/uso terapêutico , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/análise , Método Duplo-Cego , Eletrólitos/sangue , Eletrólitos/urina , Ingestão de Energia , Inibidores Enzimáticos/uso terapêutico , Fezes/química , Gastroenteropatias/induzido quimicamente , Humanos , Lactonas/efeitos adversos , Lactonas/uso terapêutico , Masculino , Minerais/análise , Minerais/urina , Obesidade/tratamento farmacológico , Obesidade/urina , Orlistate
6.
Int J Obes Relat Metab Disord ; 24(2): 187-94, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10702769

RESUMO

OBJECTIVES: After 10 d of orlistat administration (120 mg three times/day), the primary objective was to determine the drug's effect on postprandial plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities on day 10 after an oral fat-load. The secondary objectives were to determine the effects of orlistat on 12 h postprandial measures of: (1) preheparin HTGL and LPL; and (2) serum triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and free fatty acids. METHODS: Twenty-four normal-weight, healthy male volunteers were randomized to either 120 mg orlistat (n=12) or placebo (n=12) three times a day with meals for 10 d. Preheparin LPL and HTGL activities and LPL specific activity were measured in the fasted state on days 1, 5, and 10. On days 5 and 10 the study medication (orlistat or placebo) was taken at the beginning of a fat-rich breakfast and serum lipid and lipoprotein levels monitored for 12 h postprandially. On day 10, 15 min postheparin HTGL activity was measured 8 h after the fat-rich breakfast. RESULTS: No differences were found between groups in fasting levels of preheparin LPL or HTGL activity or in LPL-specific activity on days 1, 5 and 10. No difference was found between the two treatment groups in postheparin HTGL activity 8 h after the fat-rich breakfast. Also, no differences were found between the two groups in plasma triglycerides or lipoproteins. CONCLUSION: The results indicate that the oral administration of orlistat (120 mg t. i.d.) does not significantly alter plasma triglycerides or lipoproteins, and that the inhibitory effect of orlistat on lipases is limited to the gastrointestinal tract and is not manifested systemically.


Assuntos
Fármacos Antiobesidade/farmacologia , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Lipase/efeitos dos fármacos , Lipase Lipoproteica/efeitos dos fármacos , Adulto , Fármacos Antiobesidade/sangue , Fármacos Antiobesidade/farmacocinética , Método Duplo-Cego , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Ensaio de Imunoadsorção Enzimática , Humanos , Lactonas/sangue , Lactonas/farmacocinética , Lipase/sangue , Lipídeos/sangue , Lipase Lipoproteica/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Orlistate , Período Pós-Prandial , Valores de Referência
7.
J Rheumatol ; 23(3): 459-61, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8832983

RESUMO

OBJECTIVE: To describe the statistical association between serum AST and liver biopsy grade in patients with rheumatoid arthritis. METHODS: 94 patients from 3 prospectively followed cohorts underwent a total of 354 biopsies graded according to Roenigk. Blood samples for serum aminotransferase (AST) were obtained every 37.7 + or - 32.7 days (mean + or - SD) and 15.2 + or - 7.1 samples were obtained before each biopsy. For each prebiopsy interval, 4 AST functions were calculated: (1) mean, (2) maximum, (3) percentage abnormal, and (4) the presence or absence of at least one abnormality. Analysis of variance was performed to determine the effect of each of these variables on liver biopsy score. RESULTS: AST increased across biopsy grades: 26.5 IU + or - 10.7 IU (mean + or - SD) in Grade I biopsies, 28.4 + or - 10.9 in Grade II, and 35.4 + or - 21.1 in Grade IIIA (p = 0.0006, overall difference between classes). The percentage of abnormal prebiopsy AST values increased across biopsy grades: 8.7 + or - 13.9 (mean + or - SD) in Grade I biopsies, 12.3 + or - 17.5 in Grade II, and 18.6 + or - 27.1 in Grade IIIA samples [(p = 0.0014) overall difference between classes.] A mean prebiopsy AST in the abnormal range was more likely to be associated with a more abnormal liver biopsy grade (p = 0.01, Wilcoxon's rank sum test). AST values abnormal <49% of the time had a 97% specificity for a normal biopsy grade. CONCLUSION: Regular AST measurements are useful markers of hepatic histologic outcome, within the range of mostly normal histology reported here, in patients with RA receiving longterm weekly MTX.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas , Metotrexato/efeitos adversos , Adulto , Idoso , Biópsia , Estudos de Coortes , Feminino , Humanos , Hepatopatias/enzimologia , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade
8.
Arthritis Rheum ; 36(5): 613-9, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8489539

RESUMO

OBJECTIVE: To determine the effects of drug therapy (methotrexate [MTX] versus auranofin [AUR]) on radiographic progression in patients with active rheumatoid arthritis (RA). METHODS: We conducted a 9-month randomized, multicenter, double-blind trial comparing MTX and AUR. Standardized radiographs of the hands and wrists were obtained at baseline and at completion of the study. Four experienced bone radiologists graded the radiographs for erosions, joint space narrowing, erosion healing, and reparative bone formation. RESULTS: Two hundred eighty-one patients were enrolled in the study. Radiographs were available on 167 of the 183 who completed the trial. After 9 months of therapy, there was a significantly greater worsening of the erosion score in the AUR group (mean +/- SEM change of 1.67 +/- 0.4) compared with the change in the MTX group (0.60 +/- 0.3) (P = 0.040). There was also a significantly greater worsening of the joint space narrowing score in the AUR group compared with the MTX group (1.36 +/- 0.3 versus 0.42 +/- 0.2) (P = 0.007). There was no difference demonstrated between groups in healing of erosions or in reparative bone formation. CONCLUSION: The rate of radiographic progression in patients with RA, as measured by erosion score and joint space narrowing score, was demonstrated to be lower in those treated with MTX, as compared with AUR, over a 36-week period.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Auranofina/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Índice de Gravidade de Doença
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