RESUMEN
BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.
Asunto(s)
Antineoplásicos/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Sunitinib/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Sunitinib/efectos adversos , Tasa de SupervivenciaRESUMEN
BACKGROUND: GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662. METHODS: Pharmacokinetic data from 305 GIST patients included in 4 phase I-III trials were analyzed. Patients were subdivided into 6 groups according to their prior GI-surgery. Apparent clearance (CL/F) and dose-corrected steady-state plasma exposures (AUC24,ss) of sunitinib and SU12662 were estimated using a population PK approach. ANCOVA was performed to test for differences in AUC24,ss and CL/F between each surgery subgroup and controls. RESULTS: Major gastrectomy did not influence sunitinib or SU12662 exposure. The geometric mean of sunitinib and SU12662 AUC24,ss was decreased by 21% and 28% in patients with both gastrectomy and small bowel resection (n = 8) compared to controls (n = 63) for sunitinib (931 ng hr/mL (95%-CI; 676-1283) versus 1177 ng hr/mL (95%-CI; 1097-1263); p < 0.05) and SU12662 (354 ng hr/mL (95%-CI; 174-720) versus 492 ng hr/mL (95%-CI; 435-555); p < 0.05). No significant differences in exposure were observed in each of the other subgroups versus controls. CONCLUSION: In contrast to previous results for imatinib and nilotinib, gastrectomy alone does not influence sunitinib or SU12662 exposure. This should be taken into account for the treatment of gastrectomized GIST patients with TKIs. In patients who had undergone both gastrectomy and small bowel resection, sunitinib and SU12662 exposures are significantly, although clinically not relevantly, decreased.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/cirugía , Indoles/farmacocinética , Pirroles/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Ensayos Clínicos como Asunto , Femenino , Gastrectomía/efectos adversos , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Sunitinib , Adulto JovenRESUMEN
BACKGROUND: This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC). METHODS: Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR). RESULTS: Sixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure. CONCLUSIONS: Sunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy. TRIAL REGISTRATION: NCT00243503.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Indoles/administración & dosificación , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pirroles/administración & dosificación , Sunitinib , Trastuzumab , Resultado del TratamientoRESUMEN
Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (Cmax ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast ), and AUC from the time of dosing extrapolated to time infinity (AUCinf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma Cmax , AUC during a dosing interval, where tau is the length of the dosing interval (AUCtau ), and concentration immediately prior to dosing at multiple dosing (Ctrough ). When administered with enzalutamide, there was a 17% increase in Cmax , 29% increase in AUClast , and 33% increase in AUCinf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P-gp and BCRP does not require dose adjustment in this patient population.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Neoplasias de la Próstata Resistentes a la Castración , Subfamilia B de Transportador de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Benzamidas , Estudios Cruzados , Digoxina/farmacocinética , Interacciones Farmacológicas , Humanos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Nitrilos , Preparaciones Farmacéuticas , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Rosuvastatina Cálcica/farmacocinéticaRESUMEN
PURPOSE: The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. METHODS: Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. RESULTS: Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. CONCLUSION: Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.
Asunto(s)
Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Sunitinib/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Persona de Mediana Edad , Modelos Biológicos , Sunitinib/efectos adversos , Sunitinib/farmacología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Population pharmacokinetic analysis explored the pharmacokinetics of sunitinib and its primary active metabolite, SU012662, in children and evaluated the sunitinib dose(s) that produce comparable plasma exposures to adults receiving the approved daily dose. METHODS: Data were from 65 children with gastrointestinal stromal tumors (GIST) or solid tumors. Pharmacokinetic models of sunitinib and SU012662 were developed using a systematic multi-step approach employing nonlinear mixed-effects modeling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Final models were validated using visual predictive check and statistical techniques. RESULTS: The final dataset comprised 439 sunitinib and 417 SU012662 post-baseline plasma observations. Base models were characterized by two-compartment models with first-order absorption and lag time. Body surface area (BSA) was the only covariate that affected (P < 0.001) pharmacokinetic parameters for sunitinib and SU012662 and was incorporated into the final models. Bootstrap results indicated that the final models represented the final dataset adequately. Based on the final models, a sunitinib dose of ~ 20mg/m2/day in children with GIST aged 6-17 years would be expected to lead to similar total plasma exposures of sunitinib and SU012661 as a dose of 50 mg/day in an adult with GIST on schedule 4/2. CONCLUSIONS: In children with GIST or solid tumors receiving sunitinib, population pharmacokinetic analysis identified BSA as the only covariate that affected pharmacokinetic parameters and predicted a dose of ~ 20 mg/m2/day as achieving equivalent exposure to 50 mg/day in adults with GIST on schedule 4/2. TRIAL REGISTRATION: ClinicalTrials.gov identifiers (date registered): NCT01396148 (July 2011); NCT01462695 (October 2011); NCT00387920 (October 2006).
Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Sunitinib/farmacocinética , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Indoles/farmacocinética , Lactante , Masculino , Pirroles/farmacocinética , Sunitinib/administración & dosificación , Adulto JovenRESUMEN
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase. WHAT THIS STUDY ADDS: Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM: This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat. METHODS: Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed. RESULTS: Mean febuxostat C(max), AUC((0-t)), AUC((0-infinity)), t(1/2,z), CL/F and V(ss)/F values for regimens co-administration/febuxostat alone were 2.9/2.9 microg ml(-1), 9.3/9.1 microg ml(-1) h, 9.6/9.3 microg ml(-1) h, 6.5/6.1 h, 8.8/9.3 l h(-1) and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C(max), AUC((0-t)), and AUC((0-infinity)) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C(mean,24h), C(mean,48h) and CL(R) for both regimens co-administration/febuxostat alone were 216/203 micromol l(-1), 218/202 micromol l(-1) and 9.1/10.1 ml min(-1), respectively. Although serum uric acid C(mean,24h) and C(mean,48h) values were higher and CL(R) values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%-9.5%) was considered clinically significant. CONCLUSION: Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.
Asunto(s)
Supresores de la Gota/farmacocinética , Hidroclorotiazida/farmacocinética , Tiazoles/farmacocinética , Ácido Úrico/orina , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Febuxostat , Femenino , Supresores de la Gota/administración & dosificación , Supresores de la Gota/farmacología , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/farmacología , Masculino , Persona de Mediana Edad , Tiazoles/administración & dosificación , Tiazoles/farmacología , Adulto JovenRESUMEN
PURPOSE: The safety profile of sunitinib in children, including the impact of sunitinib exposure on safety endpoints, was assessed using population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models. METHODS: Data were from two clinical studies in 59 children with solid tumors (age range 2-21 years, 28 male/31 female, body weight range 16.2-100 kg, body surface are [BSA] range 0.7-2.1 m2). Analysis of covariates that affected PK and PD parameters was conducted using a nonlinear mixed-effects model. Safety and tolerability endpoints were absolute neutrophil count, hepatic transaminases, diastolic blood pressure, hemoglobin, lymphocyte count, platelet count, white blood cell count, hand-foot syndrome, fatigue, nausea, intracranial hemorrhage, and vomiting. RESULTS: The models well described the time courses of concentrations of sunitinib and its primary active metabolite SU012662, as well as safety and tolerability endpoints. In PK models for sunitinib and SU012662, BSA was the only covariate that statistically significantly affected apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). Higher BSA was associated with greater CL/F and Vc/F. No statistically significant covariates were identified in the PK-PD models. For safety endpoints that had a sufficient number of adverse events, a higher probability of adverse events was associated with higher average plasma sunitinib concentrations. CONCLUSION: In PK models, BSA was the only covariate that affected major PK parameters of sunitinib and SU012662. Based on analysis of safety and tolerability endpoints, the PK-PD relationships were mainly driven by sunitinib plasma exposures and were not affected by age, sex, respective baseline safety endpoint values, baseline Eastern Cooperative Oncology Group performance status, or body size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00387920 (registered October 13, 2006), NCT01462695 (registered October 31, 2011).
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Sunitinib/farmacocinética , Sunitinib/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias/patología , Pronóstico , Distribución Tisular , Adulto JovenRESUMEN
Using physiologically based pharmacokinetic (PBPK) modeling and simulations, this study estimated the exposure of sunitinib and its active metabolite SU012662 in pediatric patients. A PBPK simulator, SimCYP, was used to develop and validate the pharmacokinetic models. Model development employed a combined "bottom-up" and "top-down" approach to fully utilize the available in vitro or in silico experimental data and in vivo observed clinical data. First, the PBPK model for sunitinib was established, then the cytochrome P450 3A4-mediated metabolism of sunitinib was used as the input for SU012662. PBPK models were validated using pharmacokinetics of sunitinib and SU012662 from one study in adult patients with solid tumors and three clinical trials in pediatric patients with solid or gastrointestinal stromal tumors. The models were further used to predict the exposure of sunitinib and SU012662 by pediatric age groups. The PBPK models for sunitinib and SU012662 developed based on pharmacokinetic characteristics in adults successfully predicted the observed in vivo pharmacokinetics of sunitinib and SU012662 in both adults and pediatric patients. Based on the SimCYP model predictions, a daily dose of 20 mg/m2 will produce sunitinib and SU012662 total exposures in pediatric patients similar to those in adults with gastrointestinal stromal tumor treated with a clinical dose of 50 mg once daily.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacocinética , Sunitinib/farmacocinética , Administración Oral , Adolescente , Factores de Edad , Antineoplásicos/administración & dosificación , Niño , Preescolar , Ensayos Clínicos como Asunto , Simulación por Computador , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicación , Cálculo de Dosificación de Drogas , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Humanos , Indoles/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirroles/farmacocinética , Sunitinib/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Sunitinib/administración & dosificación , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib/administración & dosificación , Masculino , Supervivencia sin Progresión , Sunitinib/efectos adversos , Sunitinib/farmacocinética , Resultado del TratamientoRESUMEN
Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years. Although unbound peak concentration (C(max,u)) and area under the concentration-time curve (AUC(24,u)) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P Asunto(s)
Inhibidores Enzimáticos/farmacocinética
, Supresores de la Gota/farmacocinética
, Tiazoles/farmacocinética
, Xantina Oxidasa/antagonistas & inhibidores
, Administración Oral
, Adolescente
, Adulto
, Factores de Edad
, Anciano
, Biotransformación
, Inhibidores Enzimáticos/administración & dosificación
, Inhibidores Enzimáticos/efectos adversos
, Febuxostat
, Femenino
, Supresores de la Gota/administración & dosificación
, Supresores de la Gota/efectos adversos
, Humanos
, Hipoxantina/sangre
, Masculino
, Unión Proteica
, Factores Sexuales
, Tiazoles/administración & dosificación
, Tiazoles/efectos adversos
, Ácido Úrico/sangre
, Xantina/sangre
, Adulto Joven
RESUMEN
UNLABELLED: What is already known about this subject. Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase. What this study adds. This is the first manuscript to address the effect of food and antacid on the pharmacokinetics and/or pharmacodynamics of febuxostat. The study will determine whether the drug can be administered regardless of food or antacid. It will therefore influence how the drug should be administered. AIMS: To evaluate the effects of food or antacid on the pharmacokinetics and/or pharmacodynamics of febuxostat. METHODS: Four Phase I, two-period, crossover studies were performed in healthy male and female subjects. Subjects either received single 40-mg (n = 24), multiple 80-mg (n = 24) and single 120-mg (n = 20) doses of febuxostat in fasting and nonfasting conditions, or received single 80-mg (n = 24) doses alone or with antacid. RESULTS: Food caused a decrease in C(max) (38-49%) and AUC (16-19%) of febuxostat at different dose levels following single or multiple oral dosing with febuxostat. However, a slightly greater percent decrease in serum uric acid concentrations (58% vs. 51%) after multiple dosing with 80 mg of febuxostat under nonfasting conditions was observed, which was statistically (P < 0.05) but not clinically significant. Antacid caused a decrease in C(max) (32%), but had no effect on AUC of febuxostat. Febuxostat was safe and well tolerated in all studies. CONCLUSIONS: Even though food caused a decrease in the rate and extent of absorption of febuxostat, this decrease was not associated with a clinically significant change in febuxostat pharmacodynamic effect. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Therefore, febuxostat can be administered regardless of food or antacid intake.
Asunto(s)
Antiácidos/farmacocinética , Grasas de la Dieta/farmacocinética , Interacciones Farmacológicas/fisiología , Interacciones Alimento-Droga/fisiología , Tiazoles/farmacocinética , Adulto , Antiácidos/sangre , Antiácidos/farmacología , Estudios Cruzados , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/sangre , Ayuno , Febuxostat , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiazoles/sangre , Tiazoles/farmacologíaRESUMEN
BACKGROUND: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout. OBJECTIVE: To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects. METHODS: In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. RESULTS: Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L/h and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34-3.88 mg/dL) for all doses and was dose linear for the 10-120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity. CONCLUSION: Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.
Asunto(s)
Supresores de la Gota/farmacocinética , Tiazoles/farmacocinética , Administración Oral , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Febuxostat , Femenino , Supresores de la Gota/administración & dosificación , Supresores de la Gota/efectos adversos , Humanos , Hipoxantina/sangre , Hipoxantina/orina , Masculino , Modelos Biológicos , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Ácido Úrico/sangre , Ácido Úrico/orina , Xantina/sangre , Xantina/orina , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
To evaluate the effect of febuxostat on the pharmacokinetics of indomethacin and naproxen and vice versa, 2 multiple-dose, 3-period crossover studies were performed in healthy subjects. In study 1, subjects received febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both. In study 2, subjects received febuxostat 80 mg, naproxen 500 mg twice daily, or both. Twenty-four-hour blood samples were collected on day 5 in study 1 and day 7 in study 2. In study 1, 90% confidence intervals of geometric mean ratios for maximum plasma concentration (Cmax) and area under the curve (AUC) were within the 0.80 to 1.25 no-effect range for febuxostat and indomethacin. In study 2, 90% confidence intervals for febuxostat C(max) and AUC extended above that range, with increases of 28% and 40% in Cmax and AUC24, respectively. However, 90% confidence intervals for naproxen C(max) and AUC were within the 0.80 to 1.25 range. Febuxostat had no effect on the plasma pharmacokinetics of indomethacin and naproxen. Similarly, indomethacin had no effect on the plasma pharmacokinetics of febuxostat. Although naproxen caused an increase in plasma exposure to febuxostat, this increase is not expected to be clinically significant. Therefore, based on the plasma pharmacokinetic data in healthy subjects, febuxostat may be administered with indomethacin or naproxen with no dose adjustments for febuxostat, indomethacin, or naproxen.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Supresores de la Gota/farmacocinética , Indometacina/farmacocinética , Naproxeno/farmacocinética , Tiazoles/farmacocinética , Adulto , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacología , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Febuxostat , Femenino , Supresores de la Gota/sangre , Supresores de la Gota/farmacología , Humanos , Indometacina/sangre , Indometacina/farmacología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Naproxeno/sangre , Naproxeno/farmacología , Valores de Referencia , Tiazoles/sangre , Tiazoles/farmacologíaRESUMEN
To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once-daily 80-mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.
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Hepatopatías/metabolismo , Tiazoles/farmacocinética , Administración Oral , Adulto , Biotransformación , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Febuxostat , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiazoles/administración & dosificación , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
A simple HPLC method was developed and validated for the determination of uric acid (UA), xanthine (X) and hypoxanthine (HX) concentrations in human serum to support pharmacodynamic (PD) studies of a novel xanthine oxidase inhibitor during its clinical development. Serum proteins were removed by ultrafiltration. The hydrophilic analytes and the I.S. were eluted by 100% aqueous phosphate buffer mobile phase. The hydrophobic matrix components (late peaks) were eluted with a step gradient of a higher organic mobile phase. Validation on linearity, sensitivity, precision, accuracy, stability, and robustness of the method for PD biomarkers (UA, X, and HX) was carried out in a similar manner to that for pharmacokinetic (PK) data where applicable. Issues of selectivity for endogenous biomarker analytes and individual concentration variations were addressed during method validation. Standards were prepared in analyte-free phosphate buffer. Quality control samples were prepared in control serum from individuals not dosed with the xanthine oxidase inhibitor. The method was simple and robust with good accuracy and precision for the measurement of serum UA, X, and HX concentrations.
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Cromatografía Líquida de Alta Presión/métodos , Inhibidores Enzimáticos/farmacología , Hipoxantina/sangre , Ácido Úrico/sangre , Xantina/sangre , Humanos , Control de Calidad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Sunitinib is a multi-targeted tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma (RCC) and imatinib-resistant/intolerant gastrointestinal stromal tumors (GIST). METHODS: A meta-analysis of 10 prospective clinical studies in advanced RCC and GIST was performed to support the development of pharmacokinetic (PK) and PK/pharmacodynamic (PD) models that account for the effects of important covariates. These models were used to make predictions with respect to the PK, safety, and efficacy of sunitinib when administered on the traditional 4-weeks-on/2-weeks-off schedule (Schedule 4/2) versus an alternative schedule of 2 weeks on/1 week off (Schedule 2/1). RESULTS: The covariates found to have a significant effect on one or more of the PK or PD parameter studies included, age, sex, body weight, race, baseline Eastern Cooperative Oncology Group performance status, tumor type, and dosing schedule. The models predicted that, in both RCC and GIST patients, Schedule 2/1 would have comparable efficacy to Schedule 4/2, despite some differences in PK profiles. The models also predicted that, in both indications, sunitinib-related thrombocytopenia would be less severe when sunitinib was administered on Schedule 2/1 dosing compared with Schedule 4/2. CONCLUSION: These findings support the use of sunitinib on Schedule 2/1 as a potential alternative to Schedule 4/2 because it allows for the management of toxicity without loss of efficacy.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Indoles/farmacocinética , Indoles/uso terapéutico , Pirroles/farmacocinética , Pirroles/uso terapéutico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Peso Corporal , Carcinoma de Células Renales/patología , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Indoles/administración & dosificación , Indoles/farmacología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Pirroles/administración & dosificación , Pirroles/farmacología , Grupos Raciales , Factores Sexuales , SunitinibRESUMEN
PURPOSE: We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUCss) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer. EXPERIMENTAL DESIGN: A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes. RESULTS: Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/minute; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/minute; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCss were not predicted to be clinically relevant. CONCLUSIONS: Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin ≤ 2.1 mg/dL or AST ≤124 U/L). Clin Cancer Res; 22(23); 5722-8. ©2016 AACR.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/farmacocinética , Piridinas/farmacocinética , Anciano , Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéuticoRESUMEN
PURPOSE: This randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC). METHODS: Patients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint. RESULTS: Median progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962). CONCLUSIONS: Sunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need. TRIAL REGISTRATION: NCT00246571.
Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirroles/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Capecitabina , Quimioterapia Adyuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel , Fatiga/inducido químicamente , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Síndrome Mano-Pie/etiología , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Persona de Mediana Edad , Metástasis de la Neoplasia , Neutropenia/inducido químicamente , Paclitaxel/uso terapéutico , Pirroles/efectos adversos , Pirroles/farmacocinética , Sunitinib , Tasa de Supervivencia , Taxoides/uso terapéutico , Trombocitopenia/inducido químicamente , Neoplasias de la Mama Triple Negativas/patología , GemcitabinaRESUMEN
Absorption, metabolism, and excretion of one 80 mg oral dose of [(14)C] febuxostat ([thiazole-4-(14)C] 2-[3-cyano-4-isobutoxyphenyl]-4-methyl-5-thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M-1 (10%) and 67M-2 (11%) hydroxylated febuxostat, febuxostat acyl-glucuronide (30%), 67M-4 di-carboxylic acid (14%), 67M-1 sulfate conjugate (3%), and dehydrated 67M-1/67M-2 acyl-glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma C(max) values were observed at 0.5 hour postdose, suggesting that febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: febuxostat (85%), 67M-1 (4%), 67M-2 (5%), febuxostat acyl-glucuronide (4%), 67M-4 (1%), and 67M-1 sulfate (0.5%). Compared to total radioactivity, febuxostat accounted for 94% at C(max) and 83% of the area under the concentration-time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.