RESUMEN
PURPOSE: Commercially available enzyme-linked immunosorbent assay (ELISA) kits are often used to monitor vascular endothelial growth factor (VEGF) levels in exudative age-related macular degeneration. To test their accuracy, this study performed measurements using the ELISA kits in the presence of anti-VEGF drugs. METHODS: The concentrations of bevacizumab, pegaptanib, or ranibizumab at 28 days and aflibercept at 28 and 56 days after an injection were estimated based on previous pharmacokinetic studies. Vascular endothelial growth factor concentrations were measured with two widely used VEGF ELISA kits in the presence of anti-VEGF drugs or control mouse immunoglobulin G (IgG). The monocyte chemotactic protein-1 (MCP-1) ELISA kit was used as a non-VEGF ELISA control kit. RESULTS: The concentrations of aflibercept, bevacizumab, pegaptanib, and ranibizumab were estimated at 0.14 to 7.2, 4.9, 8.6, and 0.11 to 1.1 µg/mL, respectively. ELISA underestimated the VEGF concentration 2- to 100-fold lower in the presence of an anti-VEGF drug, except for pegaptanib, at all VEGF concentrations tested (7.8-1500 pg/mL). Vascular endothelial growth factor at 1000 pg/mL was measured as 92, 150, and 170 pg/mL in the presence of aflibercept (7.2 µg/mL), bevacizumab (4.9 µg/mL), and ranibizumab (1.1 µg/mL), respectively (all P < 0.0001), and the measured VEGF concentration decreased proportionately by 90% to 92% with aflibercept, 85% to 94% with bevacizumab, and 83% to 99% with ranibizumab. The control mouse IgG did not interfere with the measurement of VEGF. Ranibizumab did not affect the measurements with MCP-1 ELISA. CONCLUSIONS: Investigators should exercise caution when interpreting measurements of VEGF ELISA in patients being treated with an anti-VEGF drug.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Ensayo de Inmunoadsorción Enzimática/normas , Factor A de Crecimiento Endotelial Vascular/análisis , Inhibidores de la Angiogénesis/farmacocinética , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Nucleótidos/farmacología , Bevacizumab/farmacocinética , Bevacizumab/farmacología , Quimiocina CCL2/metabolismo , Semivida , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico , Ranibizumab/farmacocinética , Ranibizumab/farmacología , Juego de Reactivos para Diagnóstico/normas , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacología , Reproducibilidad de los Resultados , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Cuerpo Vítreo/metabolismoRESUMEN
PURPOSE: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. RESULTS: Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. CONCLUSION: Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/administración & dosificación , Docetaxel , Esquema de Medicación , Neutropenia Febril/inducido químicamente , Neutropenia Febril/prevención & control , Femenino , Fluorouracilo/administración & dosificación , Humanos , Hipertensión/inducido químicamente , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias/patología , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Taxoides/administración & dosificación , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
PURPOSE: We evaluated the pharmacokinetics of intravitreally injected ranibizumab and aflibercept, and their effects on VEGF in the aqueous humor of vitrectomized and nonvitrectomized macaque eyes. METHODS: Intravitreal ranibizumab (IVR; 0.5 mg/50 µL) or intravitreal aflibercept (IVA; 2 mg/50 µL) was injected into the previously vitrectomized right eyes of three macaques and nonvitrectomized right eyes of three macaques. The left eyes served as controls (nonvitrectomized, noninjected). Aqueous humor was obtained from both eyes just before injection and on days 1 and 3, and weeks 1 to 8 after IVR and IVA. The ranibizumab, aflibercept, and VEGF concentrations were measured using enzyme-linked immunosorbent assays. RESULTS: The half-lives in aqueous humor of nonvitrectomized and vitrectomized eyes were, respectively, 2.3 and 1.4 days for ranibizumab, and 2.2 and 1.5 days for aflibercept. Concentration of VEGF was decreased below the limit of detection (LOD) by IVR for 3 weeks in nonvitrectomized eyes and 1 week in vitrectomized eyes, respectively, and by IVA for 6 weeks in nonvitrectomized eyes and 4 weeks in vitrectomized eyes, respectively. In the untreated control eyes, the ranibizumab and aflibercept concentrations were below the LOD, and the VEGF aqueous concentrations remained unchanged after IVR and decreased for 3 days after IVA. CONCLUSIONS: Intravitreally injected ranibizumab and aflibercept have similar half-lives in aqueous humor and shorter half-lives in vitrectomized eyes. Compared to IVR, IVA suppresses VEGF level for a longer time period.
Asunto(s)
Humor Acuoso/metabolismo , Degeneración Macular/tratamiento farmacológico , Ranibizumab/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vitrectomía , Cuerpo Vítreo/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Animales , Humor Acuoso/efectos de los fármacos , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inyecciones Intravítreas , Macaca , Degeneración Macular/metabolismo , Degeneración Macular/patología , Masculino , Ranibizumab/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Cuerpo Vítreo/efectos de los fármacosRESUMEN
PURPOSE: To determine intraocular pharmacokinetics of aflibercept and VEGF-A in patients with neovascular age-related macular degeneration (nAMD) during a treatment period of 6 months. METHODS: Seven nonvitrectomized patients diagnosed with macular edema secondary to nAMD undergoing intravitreal injections (IVI) of aflibercept. Patients were treatment naïve at least for the last 2 months and received intravitreal injection of 2 mg aflibercept for the first time. Aqueous humor samples were obtained prior to each injection procedure during a 6-month period: three times monthly, then bimonthly. Over all 35 samples were analyzed with ELISA for unbound VEGF-A and a self-developed assay for unbound aflibercept. RESULTS: In all cases, wet AMD was inactive after IVI. Unbound aflibercept could be detected in all samples. Initial mean concentration of aflibercept was 305.4 ± 43.8 µg/mL and remained stable after the first injection with 0.8 ± 0.5 µg/mL. Initial mean level of unbound VEGF-A was 190.7 ± 26.9 pg/mL. A significant decrease of the concentration to 92.6 ± 10.2 pg/mL (P < 0.05, Wilcoxon rank sum test) after the first injection was observed. This level remained stable during further treatment. CONCLUSIONS: Levels of unbound aflibercept and unbound VEGF-A remained stable after every month and every second month of IVI. The findings of these small case series support suggestions that treatment intervals with bimonthly IVI of aflibercept are sufficient due to a detectable remaining biologic active concentration of aflibercept.
Asunto(s)
Degeneración Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Anciano de 80 o más Años , Humor Acuoso/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Inyecciones Intravítreas , Degeneración Macular/diagnóstico , Degeneración Macular/metabolismo , Masculino , Estudios Prospectivos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Agudeza VisualRESUMEN
Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF), a key regulator of angiogenesis. It binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, and, thus, prevents them from binding to and activating their cognate receptors. In the USA and EU, intravenously administered aflibercept in combination with an infusion of leucovorin, fluorouracil and irinotecan (FOLFIRI) is approved for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after treatment with an oxaliplatin-containing regimen. The efficacy of aflibercept in this indication was assessed in a multinational, pivotal phase 3 trial (VELOUR), in which the approved regimen of aflibercept 4 mg/kg every 2 weeks plus FOLFIRI significantly prolonged median overall survival by 1.44 months compared with FOLFIRI alone (primary endpoint). The addition of aflibercept also significantly prolonged progression-free survival and significantly increased the objective response rate compared with FOLFIRI alone. Addition of aflibercept to FOLFIRI was associated with anti-VEGF-related adverse events and an increased incidence of FOLFIRI-related adverse events, but the tolerability of the combination was generally acceptable in this pre-treated population. The most common grade 3 or 4 adverse events with aflibercept plus FOLFIRI included neutropenia, diarrhoea and hypertension. In conclusion, aflibercept plus FOLFIRI is a useful treatment option for patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen, with or without bevacizumab.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Metástasis de la Neoplasia , Neovascularización Patológica , Factor de Crecimiento Placentario , Proteínas Gestacionales/antagonistas & inhibidores , Proteínas Gestacionales/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor B de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor B de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Aflibercept (Eylea(®)) is an anti-vascular endothelial growth factor agent indicated for intravitreal use in the treatment of diabetic macular oedema. In patients with diabetic macular oedema, significantly greater improvements from baseline to week 52 in visual acuity were seen with intravitreal aflibercept versus macular laser photocoagulation in the phase III VISTA-DME and VIVID-DME trials, and versus intravitreal bevacizumab or ranibizumab in those with worse visual acuity at baseline (i.e. Early Treatment Diabetic Retinopathy Study letter score of <69) in the phase III PROTOCOL-T trial. Intravitreal aflibercept was generally well tolerated in patients with diabetic macular oedema. In conclusion, intravitreal aflibercept is an important new treatment for diabetic macular oedema.
Asunto(s)
Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Bevacizumab/uso terapéutico , Retinopatía Diabética/complicaciones , Humanos , Terapia por Luz de Baja Intensidad/métodos , Edema Macular/complicaciones , Edema Macular/radioterapia , Ranibizumab/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
INTRODUCTION: Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. Aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. AREAS COVERED: A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. Aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. EXPERT OPINION: In this challenging field, aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment. Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Humanos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To determine intraocular pharmacokinetic properties of intravitreally injected vascular endothelial growth factor (VEGF)-Trap in a rabbit model. METHODS: VEGF-Trap was intravitreally injected in 18 rabbit eyes. Eyes were enucleated 1 h and 1, 2, 5, 14, and 30 days after injections and immediately frozen at -80 °C. Concentration of VEGF-Trap in vitreous, aqueous humor, and retina/choroid was determined using an indirect enzyme-linked immunosorbent assay and analyzed to obtain pharmacokinetic properties. RESULTS: Maximum concentration of VEGF-Trap was achieved at 1 h in all three tissues. A one-compartment model of distribution was selected as the final model for all tissues studied. Estimated half-life of VEGF-Trap in vitreous, aqueous humor, and retinal/choroid was 87.1, 36.8, and 35.0 h, respectively, and estimated mean residence time was 125.7, 53.1, and 50.5 h, respectively. Area under the curve from time 0 to the end point was 10009.8, 3945.1, and 1189.3, respectively. Total exposure of the aqueous humor and retina/choroid to VEGF-Trap was 39.4% and 11.9% of vitreous exposure, respectively. CONCLUSION: The vitreous half-life of VEGF-Trap is 3.63 days. This is shorter than that of bevacizumab (6.99 days) and longer than that of ranibizumab (2.51 days), as shown in studies using the same experimental settings. The concentration of VEGF-Trap peaked at 1 h after injections in all eye tissues studied.
Asunto(s)
Inhibidores de la Angiogénesis/farmacocinética , Humor Acuoso/metabolismo , Coroides/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Retina/metabolismo , Cuerpo Vítreo/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Área Bajo la Curva , Semivida , Inyecciones Intravítreas , Modelos Animales , Conejos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificaciónRESUMEN
PURPOSE: It is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys. METHODS: The kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm. RESULTS: Compared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased. CONCLUSION: Surprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.
Asunto(s)
Inhibidores de la Angiogénesis , Glomérulos Renales/metabolismo , Ranibizumab , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Evaluación Preclínica de Medicamentos , Femenino , Inyecciones Intravítreas , Macaca fascicularis , Masculino , Ranibizumab/efectos adversos , Ranibizumab/farmacocinética , Ranibizumab/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5â mg), bevacizumab (1.25â mg), or aflibercept (2.0â mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10â pg/mL) as early as 3â h postdose until ≥7â days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4â pg/mL compared with baseline of 17â pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.
Asunto(s)
Inhibidores de la Angiogénesis/farmacocinética , Anticuerpos Monoclonales Humanizados/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Degeneración Macular Húmeda/metabolismo , Anciano , Bevacizumab , Disponibilidad Biológica , Ensayo de Inmunoadsorción Enzimática , Femenino , Semivida , Humanos , Inyecciones Intravítreas , Masculino , Estudios Prospectivos , Ranibizumab , Distribución Tisular , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/sangre , Cuerpo Vítreo/metabolismoRESUMEN
Aflibercept is a fully human, recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF) family members, including VEGF-A, VEGF-B and placental growth factor (P1GF), thereby inhibiting downstream signalling mediated by these ligands. Aflibercept binds all isoforms of VEGF-A with high affinity, and a markedly higher affinity than that of ranibizumab or bevacizumab. A formulation of aflibercept developed specifically for intravitreal injection (Eylea(®)) is approved for use in several countries for the treatment of patients with macular oedema secondary to central retinal vein occlusion (CRVO). In clinical trials (GALILEO and COPERNICUS) in patients with this condition, intravitreal aflibercept 2 mg every month improved best corrected visual acuity (BCVA), as measured by the proportion of study eyes with a gain of ≥15 Early Treatment Diabetic Retinopathy Study letters from baseline, significantly more than sham injections at week 24 (primary analysis). The significant improvements achieved with intravitreal aflibercept compared with sham in the first 6 months were maintained in the second 6 months with as-needed (prn) dosing and monthly monitoring. Continued prn dosing with a reduced monitoring frequency was associated with decreased improvements. More data are needed to confirm the optimal monitoring frequency for use with prn dosing, subsequent to initial monthly injections, in order to maintain long-term efficacy. Intravitreal aflibercept was generally well tolerated in clinical trials and there is little potential for systemic drug accumulation. Thus, intravitreal aflibercept is an effective and generally well tolerated agent that extends the options available for the treatment of macular oedema secondary to CRVO.
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Edema Macular/complicaciones , Edema Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Oclusión de la Vena Retiniana/complicaciones , Humanos , Edema Macular/fisiopatología , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacología , Resultado del TratamientoRESUMEN
Current therapeutic antiangiogenic biologics used for the treatment of pathological ocular angiogenesis could have serious side effects due to their interference with normal blood vessel physiology. Here, we report the generation of novel antivascular endothelial growth factor-A (VEGF) biologics, termed VEGF "Sticky-traps," with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects. Using genetic and pharmacological approaches, we demonstrated that Sticky-traps could locally inhibit angiogenesis to at least the same extent as the original VEGF-trap that also gains whole-body access. Sticky-traps did not cause systemic effects, as shown by uncompromised wound healing and normal tracheal vessel density. Moreover, if injected intravitreally, recombinant Sticky-trap remained localized to various regions of the eye, such as the inner-limiting membrane and ciliary body, for prolonged time periods, without gaining access either to the photoreceptors/choriocapillaris area or the circulation. These unique pharmacological characteristics of Sticky-trap could allow for safe treatment of pathological angiogenesis in patients with diabetic retinopathy and retinopathy of pre-maturity.
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Productos Biológicos/metabolismo , Ojo/efectos de los fármacos , Neovascularización Patológica/prevención & control , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Productos Biológicos/efectos adversos , Productos Biológicos/farmacocinética , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Bootstrap methods are used in many disciplines to estimate the uncertainty of parameters, including multi-level or linear mixed-effects models. Residual-based bootstrap methods which resample both random effects and residuals are an alternative approach to case bootstrap, which resamples the individuals. Most PKPD applications use the case bootstrap, for which software is available. In this study, we evaluated the performance of three bootstrap methods (case bootstrap, nonparametric residual bootstrap and parametric bootstrap) by a simulation study and compared them to that of an asymptotic method (Asym) in estimating uncertainty of parameters in nonlinear mixed-effects models (NLMEM) with heteroscedastic error. This simulation was conducted using as an example of the PK model for aflibercept, an anti-angiogenic drug. As expected, we found that the bootstrap methods provided better estimates of uncertainty for parameters in NLMEM with high nonlinearity and having balanced designs compared to the Asym, as implemented in MONOLIX. Overall, the parametric bootstrap performed better than the case bootstrap as the true model and variance distribution were used. However, the case bootstrap is faster and simpler as it makes no assumptions on the model and preserves both between subject and residual variability in one resampling step. The performance of the nonparametric residual bootstrap was found to be limited when applying to NLMEM due to its failure to reflate the variance before resampling in unbalanced designs where the Asym and the parametric bootstrap performed well and better than case bootstrap even with stratification.
Asunto(s)
Simulación por Computador , Modelos Biológicos , Modelos Estadísticos , Dinámicas no Lineales , Incertidumbre , Inhibidores de la Angiogénesis/farmacocinética , Humanos , Población , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Programas InformáticosRESUMEN
OBJECTIVE: Review pharmacology, pharmacokinetics, efficacy, and safety of ziv-aflibercept in combination with FOLFIRI for treatment of metastatic colorectal cancer (mCRC) resistant to or progressed following oxaliplatin-containing regimens. DATA SOURCES: Articles indexed in PubMed (1948-August 2013), TOXLINE (2001-August 2013), and Google Scholar as well as meeting abstracts were identified using the search terms ziv-aflibercept and colorectal cancer. STUDY SELECTION AND DATA EXTRACTION: Available English-language articles DATA SYNTHESIS: Ziv-aflibercept, a selective vascular endothelial growth factor antagonist, was evaluated as monotherapy for treatment of mCRC in a phase 2 study and added to FOLFIRI in a phase 3 trial. Patient response to ziv-aflibercept as monotherapy did not reach statistical significance. Results suggest that response to ziv-aflibercept treatment is not influenced by prior bevacizumab therapy. A phase 3 trial compared the safety and efficacy of ziv-aflibercept plus FOLFIRI with placebo plus FOLFIRI in patients with mCRC who experienced disease progression on an oxaliplatin-containing regimen. Patients in the ziv-aflibercept arm had a median overall survival of 13.5 months, versus 12.06 months for those receiving placebo (hazard ratio [HR] = 0.817, 95% CI = 0.713 to 0.937). Progression-free survival for patients receiving ziv-aflibercept was higher compared with placebo (HR = 0.758; 95% CI = 0.661 to 0.869). The most common adverse effects observed were anemia, diarrhea, and neutropenia. CONCLUSIONS: Ziv-aflibercept is a safe and effective option in combination with FOLFIRI for the treatment of mCRC in patients who progress on oxaliplatin-containing therapy. Superiority over other antiangiogenic treatment has not been established.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacologíaAsunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto/métodos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/metabolismo , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Aflibercept (Zaltrap®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. METHODS: Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. RESULTS: An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL(f)) and bound aflibercept (CL(b)) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V(p)) and bound (V(b)) aflibercept were similar (~4 L). CL f and V(p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL(f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. CONCLUSIONS: Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.
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Inhibidores de la Angiogénesis/farmacocinética , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/metabolismo , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Peso Corporal , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Estudios de Cohortes , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Simulación por Computador , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismo , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/uso terapéutico , Caracteres Sexuales , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5-25 mg/kg) up to 3-7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0-16) and systemic bioluminescent imaging (days 0-28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration-time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h(-1). This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.
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Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Antineoplásicos/farmacología , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Femenino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Ratones SCID , Receptores de Factores de Crecimiento Endotelial Vascular/farmacología , Proteínas Recombinantes de Fusión/farmacología , Resultado del TratamientoRESUMEN
Angiogenesis is the process of formation of new blood vessels due to over expression of VEGF (vascular endothelial growth factor) which plays a critical role in the growth and development of all solid tumor types. With the advancement in understanding of tumor angiogenesis and VEGF, there have been a number of agents developed to target VEGF for the treatment of cancer. These targeted agents can affect downstream VEGF signal transduction by unique mechanisms at different cellular and extracellular levels. FDA has recently approved Aflibercept or VEGF-Trap in August 2012 for the treatment of colorectal cancer. It is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting VEGF-A, VEGF-B and placental growth factor. VEGF-Trap exerts its antiangiogenic effects through regression of tumor vasculature, remodelling or normalization of surviving vasculature and inhibition of new tumor vessel growth. In this review, pre-clinical and clinical data have been summarized for aflibercept alone and in combination with chemotherapy to explore its efficacy and benefits in ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, glioblastoma, adenocarcinoma and renal cell cancer xenograft models.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacocinética , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo Asiatico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Administración Intravenosa , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/farmacocinética , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/farmacocinética , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Bevacizumab es capaz de atravesar las barreras oculares en la administración intravítrea y generar concentraciones plasmáticas que producen un efecto inhibidor del factor de crecimiento endotelial vascular (VEGF) en el plasma, con lo que no pueden descartarse efectos sistémicos. El hecho de que se trate de una inmunoglobulina G (IgG) completa explica este fenómeno a través de la participación de receptores FcRn, cuya fijación, al igual quela de cualquier otra IgG, implica su internalización, el traslado a la membrana celular, y la externalización al espacio extracelular y a la sangre. Este proceso ocurre en cualquier tejido que disponga de células que expresen este tipo de receptor, entre los que se encuentra el ojo. Además, la ausencia de una formulación específica para la administración intravítrea supone la manipulación de la formulación i.v., que conlleva la generación de agregados de tamaño elevado, riesgo potencial de problemas con la esterilidad de la solución y de reducción del efecto farmacológico. Ranibizumab no es una IgG completa, sino sólo una fracción variable de ésta dotada de actividad anti-VEGF. La ausencia en su estructura de fracción constante implica la imposibilidad de fijación al receptor FcRn y, con ello, la ausencia de proceso de transporte hasta las angre. Por consiguiente, su biodisponibilidad sistémica tras la administración intravítrea es nula, lo que evita efectos en otros territorios del cuerpo humano distintos al ojo. Además, la formulación está preparada de forma específica para la administración intraocular, lo que evita problemas derivados de la manipulación. La experiencia acumulada con estos fármacos permite trasladar las diferencias existentes en la farmacología a la práctica cotidiana, en referencia a la eficacia y tolerabilidad de estos fármacos(AU)
Bevacizumab is able to cross ocular barriers when administered through the intravitreal route and to generate plasma concentrations with an inhibitory effect on plasma vascular endothelial growth factor (VEGF). Consequently, systemic effects cannot be ruled out. The fact that bevacizumab is a full-length IgG explains this phenomenon through the participation of FcRn receptors, whose binding-like that of all IgGs-implies their internalization, transfer to the cell membrane, and externalization to the intracellular space and blood. This process occurs in all tissues with cells expressing this type of receptor, such as the eye. Moreover, because of the absence of a specific formulation for intravitreal administration, an intravenous formulation must be manipulated, generating large-sized aggregates, leading to potential problems of the solutions sterility and reducing the pharmacological effect. Ranibizumab is not a full-length IgG but is rather a variable IgG fraction with anti-VEG Factivity. Because of the absence of a constant fraction in its structure, this drug cannot bind to the FcRn receptor and, as a result, cannot be transported to the blood. Consequently, its systemic bioavailability after intravitreal administration is nil, thus avoiding effects in parts of the body other than the eye. Moreover, the formulation is specifically prepared for intraocular administration, avoiding problems due to manipulation. The experience gained with these drugs allows the differences in their efficacy and tolerability to be transferred to daily practice(AU)