RESUMO
PURPOSE: We evaluated the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients. PATIENTS AND METHODS: Patients were randomly assigned to either placebo or pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m(2) docetaxel. The primary end point was the percentage of patients developing febrile neutropenia (defined as body temperature >/= 38.2 degrees C and neutrophil count < 0.5 x 10(9)/L on the same day of the fever or the day after). Secondary end points were incidence of hospitalizations associated with a diagnosis of febrile neutropenia, intravenous (IV) anti-infectives required for febrile neutropenia, and the ability to maintain planned chemotherapy dose on time. Patients with febrile neutropenia were converted to open-label pegfilgrastim in subsequent cycles. RESULTS: Nine hundred twenty-eight patients received placebo (n = 465) or pegfilgrastim (n = 463). Patients receiving pegfilgrastim, compared with patients receiving placebo, had a lower incidence of febrile neutropenia (1% v 17%, respectively; P < .001), febrile neutropenia-related hospitalization (1% v 14%, respectively; P < .001), and use of IV anti-infectives (2% v 10%, respectively; P < .001). The percentage of patients receiving the planned dose on time was similar between patients receiving pegfilgrastim and patients who initially received placebo (80% and 78%, respectively), as would be expected of the study design. Pegfilgrastim was generally well tolerated and safe, and the adverse events reported were typical of this patient population. CONCLUSION: First and subsequent cycle use of pegfilgrastim with a moderately myelosuppressive chemotherapy regimen markedly reduced febrile neutropenia, febrile neutropenia-related hospitalizations, and IV anti-infective use.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Febre/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/prevenção & controle , Adulto , Idoso , Antineoplásicos/efeitos adversos , Neoplasias da Mama/complicações , Docetaxel , Método Duplo-Cego , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Polietilenoglicóis , Proteínas Recombinantes , Taxoides/efeitos adversosRESUMO
Following induction therapy and 4 g/m(2) cyclophosphamide, a single dose of 12 mg polyethyleneglycol-conjugated G-CSF (pegfilgrastim; n=12) or daily doses of unconjugated G-CSF (8.5 mug/kg/day) (n=12) were administered to myeloma patients. Pegfilgrastim was associated with an earlier leukocyte recovery (12 vs 14 days) and peripheral blood CD34+ cell peak (12 vs 15 days). The peripheral blood CD34+ cell peak was lower in the pegfilgrastim group (78 vs 111/mul). Following high-dose melphalan (200 mg/m(2)) and autografting, leukocyte and platelet reconstitution was similar in both groups and stable blood counts were observed 100 days post transplant. In summary, a single dose of pegfilgrastim after chemotherapy is capable of mobilizing a sufficient number of CD34+ cells for successful autografting with early engraftment and sustained hematological reconstitution in patients with myeloma. These data provide the basis for randomized studies evaluating the optimal dose and time of pegfilgrastim as well as long-term outcome in larger cohorts of patients.
Assuntos
Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Adulto , Antígenos CD34/biossíntese , Plaquetas/citologia , Ciclofosfamida/farmacologia , Feminino , Filgrastim , Humanos , Cinética , Leucaférese , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Melfalan/farmacologia , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Polietilenoglicóis/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Recombinantes , Fatores de TempoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Feminino , Febre , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Infecções , Estudos Multicêntricos como Assunto , Polietilenoglicóis , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Fatores de Risco , Resultado do TratamentoRESUMO
Chemotherapy-induced neutropenia is a frequent complication in cancer patients receiving myelosuppressive chemotherapy. Chemotherapy-induced neutropenia can result in febrile neutropenia and potentially life-threatening infections requiring hospitalization and intravenous anti-infectives. Chemotherapy dose may be reduced or delayed as a result of chemotherapy-induced neutropenia, which can negatively impact treatment outcomes. Granulocyte colony-stimulating factors, such as filgrastim, stimulate neutrophil production and can therefore reduce the incidence and severity of chemotherapy-induced neutropenia. Filgrastim undergoes rapid renal clearance and needs to be administered daily. The development of pegfilgrastim represents a significant advance in the management of chemotherapy-induced neutropenia as the longer serum half-life allows once-per-chemotherapy administration, and evidence supports increased prophylactic effectiveness in reducing the incidence of febrile neutropenia. This paper reviews the development of pegfilgrastim and summarizes recent clinical data on the use of this simple, effective and well-tolerated option for the management of chemotherapy-induced neutropenia in patients with cancer.
Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neutropenia/prevenção & controle , Ensaios Clínicos como Assunto , Filgrastim , Humanos , Neoplasias/complicações , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Drug therapy plays a significant role in causing neutropenia. The neutropenia may be immune mediated or due to direct inhibition of the bone marrow precursors. Recently, due to wide use of chemotherapy, febrile neutropenia has become a common and devastating problem. Neutropenia predisposes to many bacterial and fungal infections with organisms including gram negative bacilli such as E. coli, Klebsiella, and Pseudomonas; gram positive organisms such as Staphylococcus, Streptococcus viridans, and Enterococcus species; and fungi, like Candida and Aspergillus. In addition to the customary supportive care for neutropenic patients, therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) (filgrastim) has been shown to be beneficial. Filgrastim was a significant advance in the management of drug induced neutropenia in the past decade, but therapy with pegfilgrastim (a pegylated, long-acting form of filgrastim) ushers in the current decade. Pegfilgrastim (Neulasta) is administered as a single s.c. injection once per chemotherapy cycle. This results in fewer injections, fewer patient visits to the physician's office, and better patient compliance with therapy.
Assuntos
Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Neutropenia/induzido quimicamente , Infecções Bacterianas/complicações , Infecções Fúngicas do Sistema Nervoso Central/complicações , Gerenciamento Clínico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/diagnóstico , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas RecombinantesRESUMO
Neutropenia is a significant hematologic complication induced by cytotoxic chemotherapy. The clinical consequences of chemotherapy-induced neutropenia are often severe and can be potentially life-threatening. Patients who develop febrile neutropenia often need to be hospitalized, reducing their quality of life and increasing costs. Neutropenia can also compromise the ability to deliver chemotherapy at the full dose and on schedule. To help prevent the occurrence of neutropenia, patients with a high risk of developing chemotherapy-related infections may be given prophylactic colony-stimulating factors. Filgrastim is a recombinant human granulocyte colony-stimulating factor that has been widely used (in over 3 million patients) for over 12 years in the management of neutropenia. Pegfilgrastim is an approved, long-acting, next generation of granulocyte colony-stimulating factor that has similar clinical benefits to filgrastim but has novel pharmacokinetic properties. Pegfilgrastim shows at least comparable safety and efficacy to filgrastim, with the added benefit of simplified once-per-chemotherapy-cycle dosing. In addition, two randomized, controlled pivotal trials have shown that a single dose of pegfilgrastim given once per cycle led to a lower observed incidence of febrile neutropenia following myelosuppressive chemotherapy, compared with daily injections of filgrastim. Clinical trials are currently expanding the clinical experience with pegfilgrastim in a variety of solid tumors and hematologic malignancies. In addition to prevention of chemotherapy-induced neutropenia in 21- and 28-day regimens, future studies are examining the suitability of pegfilgrastim in dose-dense therapy and other cancer settings.
Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/imunologia , Neutropenia/tratamento farmacológico , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas RecombinantesRESUMO
BACKGROUND: Patients with cancer must make frequent visits to the clinic not only for chemotherapy but also for the management of treatment-related adverse effects. Neutropenia, the most common dose-limiting toxicity of myelosuppressive chemotherapy, has substantial clinical and economic consequences. Colony-stimulating factors such as filgrastim and pegfilgrastim can reduce the incidence of neutropenia, but the clinic visits for these treatments can disrupt patients' routines and activities. METHODS: We surveyed patients to assess how clinic visits for treatment with chemotherapy and the management of neutropenia affect their time and activities. RESULTS: The mean amounts of time affected by these visits ranged from approximately 109 hours (hospitalization for neutropenia) and 8 hours (physician and chemotherapy) to less than 3 hours (laboratory and treatment with filgrastim or pegfilgrastim). The visits for filgrastim or pegfilgrastim were comparable in length, but treatment with filgrastim requires several visits per chemotherapy cycle and treatment with pegfilgrastim requires only 1 visit. CONCLUSIONS: This study provides useful information for future modelling of additional factors such as disease status and chemotherapy schedule and provides information that should be considered in managing chemotherapy-induced neutropenia.
Assuntos
Atividades Cotidianas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Qualidade de Vida , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas Recombinantes , Perfil de Impacto da Doença , Fatores de TempoRESUMO
Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality. Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules, with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent. The addition of a polyethylene glycol (PEG) moiety to filgrastim (rmetHu-G-CSF, Neupogen) resulted in the development of pegfilgrastim. Pegfilgrastim is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia. The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation. Pegylation increases the size of filgrastim so that it becomes too large for renal clearance. Consequently, neutrophil-mediated clearance predominates in elimination of the drug. This extends the median serum half-life of pegfilgrastim to 42 hours, compared with between 3.5 and 3.8 hours for Filgrastim, though in fact the half-life is variable, depending on the absolute neutrophil count, which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells. The clearance of the molecule is thus dominated by a self-regulating mechanism. Pegfilgrastim retains the same biological activity as filgrastim, and binds to the same G-CSF receptor, stimulating the proliferation, differentiation and activation of neutrophils. Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim. In clinical trials, patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto , Desenho de Fármacos , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/química , Fator Estimulador de Colônias de Granulócitos/fisiologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas RecombinantesRESUMO
As the population ages, a dramatic increase in the number of cases of cancer is expected and the need for supportive-care agents, those used to ameliorate some of the side effects of cancer or its treatment, becomes more urgent. At present, supportive-care products are available and new agents are being developed with novel mechanisms of action or modifications of existing agents that improve performance. Because of the urgent need for such products, efficient development is required to deliver useful products to patients as rapidly as possible. This chapter uses actual examples to illustrate the stages of drug development, phase I through phase 3.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/análogos & derivados , Eritropoetina/uso terapêutico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/tratamento farmacológico , Neutropenia/tratamento farmacológico , Cuidados Paliativos/métodos , Estomatite/tratamento farmacológico , Anemia/etiologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Darbepoetina alfa , Aprovação de Drogas/legislação & jurisprudência , Desenho de Fármacos , Avaliação de Medicamentos/métodos , Fator 7 de Crescimento de Fibroblastos , Filgrastim , Humanos , Neoplasias/complicações , Neoplasias/terapia , Cuidados Paliativos/tendências , Polietilenoglicóis , Qualidade de Vida , Proteínas Recombinantes , Estomatite/etiologia , Estados UnidosRESUMO
Twenty-nine patients with non-Hodgkin's lymphoma received a single subcutaneous injection of 6 mg pegfilgrastim approximately 24 h after the start of CHOP chemotherapy. The safety of pegfilgrastim in this patient population was determined by reports of adverse events. The pharmacokinetics of pegfilgrastim were characterized and the duration of grade 4 neutropenia, time to absolute neutrophil count (ANC) recovery to > or = 2.0 x 10(9)/l, neutrophil nadir, and incidence of febrile neutropenia were determined in the first 21-day chemotherapy cycle. The incidence of grade 4 neutropenia in cycle 1 was 43% with a mean (SD) duration of grade 4 neutropenia value of 1.0 (1.4) day. No apparent relationship between the duration of grade 4 neutropenia and body weight was observed. The median [quartiles] time to ANC recovery was 10 [9, 11] days. The incidence of febrile neutropenia was 11%. No unexpected adverse events were reported and no patient developed antibodies to pegfilgrastim. Serum concentration of pegfilgrastim reached a maximum (median [quartiles]) of 128 [58, 159] ng/ml at approximately 24 h after administration, and was followed by a second smaller peak (median [quartiles]) of 10.6 [3.0, 20.5] ng/ml at the time of the neutrophil nadir. After the second peak, concentration of pegfilgrastim declined linearly with a median terminal half-life of approximately 42 h.
Assuntos
Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Neutropenia/tratamento farmacológico , Neutrófilos/fisiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Humanos , Incidência , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Polietilenoglicóis , Prednisona/uso terapêutico , Proteínas Recombinantes , Segurança , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
OBJECTIVE: To discuss clinical data on the utility of 2 colony-stimulating factors (CSFs), filgrastim and pegfilgrastim, in reducing the risk and incidence of neutropenic complications with chemotherapy. DATA SOURCES: This article reviews the data from the clinical studies for both pegfilgrastim and filgrastim. Additionally, data from large, population-based retrospective analyses on the clinical and economic consequences of chemotherapy- induced neutropenia (CIN) are reviewed. CONCLUSIONS: CIN remains an undertreated condition despite the evidence of its danger. Pivotal trials show that CSFs like pegfilgrastim and filgrastim are safe and effective in reducing both the incidence and duration of CIN and febrile neutropenia in patients who have been treated with myelosuppressive chemotherapy. Approximately 11 daily injections of filgrastim per chemotherapy cycle are required to achieve this clinical end point. Pegfilgrastim provides all the clinical benefits of daily filgrastim for managing CIN with a single dose per chemotherapy cycle.
Assuntos
Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/prevenção & controle , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto , Esquema de Medicação , Determinação de Ponto Final , Febre/induzido quimicamente , Febre/etiologia , Febre/prevenção & controle , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Injeções , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Pegfilgrastim is composed of the protein filgrastim to which a 20-kDa polyethylene glycol (PEG) is covalently bound at the N-terminal residue resulting in decreased renal clearance and increased plasma half-life compared with filgrastim. This open-label, randomized, phase 2 study compared two doses of single administration pegfilgrastim (60 and 100 microg/kg) with daily doses of filgrastim (5 microg/kg/day) or no cytokine treatment after standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy for non-Hodgkin's lymphoma in 50 elderly patients. The primary endpoint was the duration of grade 4 (severe) neutropenia (absolute neutrophil count < 0.5 x 10(9)/l) in cycle 1. Duration of grade 4 neutropenia in cycle 1 was 2.2 (SD 1.2), 1.5 (SD 1.1), 0.8 (1.2) and 5.0 (2.0) days for patients who received pegfilgrastim 60 microg/kg, pegfilgrastim 100 microg/kg, filgrastim 5 microg/kg and no cytokine, respectively. The baseline characteristics of the pegfilgrastim and filgrastim groups were imbalanced with increased bone-marrow involvement and prior therapy in the former. When the treatment groups were balanced for these risk factors, duration of grade 4 neutropenia was comparable with 2.0 and 3.0 vs. 0.6 and 0.5 days for pegfilgrastim 100 microg/kg and filgrastim patients with and without these risk factors, respectively. The incidence of febrile neutropenia (defined as ANC < 0.5 x 10(9)/l and temperature > 38.2degrees C) was low (10% of patients). Pegfilgrastim was well tolerated with a safety profile similar to daily filgrastim. Once per chemotherapy cycle administration of pegfilgrastim was comparable to filgrastim in this clinical setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Neutropenia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Europa (Continente) , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Linfoma não Hodgkin/radioterapia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Dor/induzido quimicamente , Polietilenoglicóis , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Proteínas Recombinantes , Segurança , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosAssuntos
Antineoplásicos/efeitos adversos , Fatores Estimuladores de Colônias/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Neoplasias/imunologia , Polietilenoglicóis , Qualidade de Vida , Proteínas RecombinantesRESUMO
Filgrastim (r-metHuG-CSF) was approved in the United States in 1991 for use in decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy. Colony-stimulating factors such as filgrastim are a significant advance in the supportive care of patients with cancer. However, because of its short half-life, filgrastim requires daily dosing by injection to maintain its effects on the bone marrow. Pegfilgrastim (Neulasta; Amgen, Thousand Oaks, CA) is a longer-acting, self-regulating form of filgrastim created by the covalent linkage of a 20-kd polyethylene glycol molecule to the N-terminal of the filgrastim molecule. The molecular characteristics of pegfilgrastim result in a longer terminal half-life, making once-per-chemotherapy-cycle administration possible. The results from two randomized double-blind phase III clinical trials in patients with breast cancer treated with myelosuppressive chemotherapy showed that a single dose of pegfilgrastim provides neutrophil support comparable with that provided by an average of 11 daily injections of filgrastim. Pegfilgrastim has also been shown to be comparable to filgrastim in reducing neutropenic complications in patients treated with chemotherapy for lymphoma. Data from three clinical trials have been presented: a randomized controlled trial in elderly patients treated with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) for relapsed or refractory non-Hodgkin's lymphoma; a randomized controlled trial in patients treated with ESHAP (etoposide/methylprednisolone/cisplatin/cytarabine) for relapsed or refractory lymphoma; and a study in patients with newly diagnosed non-Hodgkin's lymphoma. The safety profile of pegfilgrastim is comparable to that of filgrastim in the clinical settings studied to date. The once-per-cycle administration of pegfilgrastim may improve patient quality of life because it is less disruptive to patients and caregivers, and increase adherence because no doses are missed, thus further advancing the management of chemotherapy-induced neutropenia and its consequences.
Assuntos
Antineoplásicos/efeitos adversos , Fatores Estimuladores de Colônias/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Ensaios Clínicos como Assunto , Fatores Estimuladores de Colônias/administração & dosagem , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Polietilenoglicóis , Proteínas RecombinantesAssuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/tratamento farmacológico , Ensaios Clínicos como Assunto , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas RecombinantesRESUMO
Pegylation, the technology of polyethylene glycol (PEG) conjugation, holds significant promise in maintaining effective plasma concentrations of systemically administered drugs that might otherwise be hampered in vivo by a number of factors, such as rapid elimination by the kidneys. Mobile, nontoxic PEG chains can be conjugated to biotherapeutics, increasing their hydrodynamic volume, which can in turn prolong their plasma retention time, increase their solubility, and shield antigenic determinants on the drug from detection by the immune system. Attaching PEG molecules for optimal pharmacokinetics without obstructing the active sites that are essential for drug efficacy is a major challenge in pegylation. Current pegylation technology uses linkerless conjugation methods to produce coupling without added toxicity or immunogenicity, and may keep the innate surface charge of the pegylated molecule intact. In addition to controlling the size and complexity of PEG molecules, the attachment site can be manipulated to avoid steric hindrance of the drug's active receptor-recognition or substrate-interaction site. A few pegylated drugs have been engineered to have an improved pharmacokinetic profile with preserved bioactivity. They often have prolonged steady plasma concentrations in vivo, thereby making a reduced number of doses possible. Other interesting effects have also emerged, such as the self-regulating pharmacokinetics of pegfilgrastim, a pegylated version of the granulocyte colony-stimulating factor filgrastim that is administered for management of chemotherapy-induced neutropenia. The improved dosing schedule, with longer intervals between administrations of the pegylated agents, will improve compliance and quality of life in patients with chronic disease.
Assuntos
Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Polietilenoglicóis/química , Animais , Produtos Biológicos/farmacocinética , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Humanos , Oncologia , Proteínas Recombinantes , Tecnologia FarmacêuticaRESUMO
Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) with a long half-life and sustained duration of action. Pegfilgrastim is created with pegylation technology, whereby a 20-kD polyethylene glycol moiety is conjugated to filgrastim (recombinant human G-CSF), resulting in a larger molecule. Consequently, its renal clearance by glomerular filtration is minimized, making neutrophil-mediated clearance the predominant route of elimination. Preclinical animal data have shown that the clearance of pegfilgrastim depends on dosage and absolute neutrophil count, with pegfilgrastim having a longer circulating half-life and more sustained duration of action than filgrastim. The biologic effect of pegfilgrastim is prolonged in a neutropenic setting because few mature neutrophils are available to mediate its elimination. Clinical trials have suggested that neutrophil-mediated clearance of pegfilgrastim may be self-regulating and may therefore be specific to each patient's hematopoietic recovery.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacocinética , Animais , Antineoplásicos/efeitos adversos , Área Sob a Curva , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/farmacologia , Meia-Vida , Humanos , Taxa de Depuração Metabólica , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas RecombinantesRESUMO
The major dose-limiting toxicity associated with myelosuppressive chemotherapy is neutropenia, which can be ameliorated with proactive administration of granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim is a long-acting G-CSF, recently approved by the Food and Drug Administration. The efficacy and safety of pegfilgrastim administered once/chemotherapy cycle have been evaluated in clinical trials involving patients treated with myelosuppressive chemotherapy for breast cancer, lung cancer, non-Hodgkin's lymphoma, and Hodgkin's disease. Two pivotal phase III trials in patients with breast cancer showed that pegfilgrastim is as effective as filgrastim regarding the primary efficacy end point, which was duration of grade 4 (severe) neutropenia in cycle 1 of myelosuppressive chemotherapy. Secondary end points were the frequency of fever with neutropenia (febrile neutropenia), duration of neutropenia in cycles 2-4, depth of the absolute neutrophil count (ANC) nadir, and time to ANC recovery in cycles 1-4. Once/cycle pegfilgrastim 100 microg/kg or 6 mg was as safe and effective as daily filgrastim 5 microg/kg in reducing the frequency and duration of severe neutropenia. A trend toward a greater reduction in the overall frequency of febrile neutropenia with pegfilgrastim was observed. The availability of pegfilgrastim simplifies the use of prophylactic G-CSF, with the potential to increase patient convenience and adherence in management of chemotherapy-induced neutropenia.
Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/tratamento farmacológico , Ensaios Clínicos como Assunto , Filgrastim , Fator Estimulador de Colônias de Granulócitos/análogos & derivados , Humanos , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas RecombinantesRESUMO
Daily administration of filgrastim decreases the duration of severe neutropenia in the clinical setting. A sustained-duration form of filgrastim, pegfilgrastim, significantly reduces scheduling protocols to a single injection per chemotherapy cycle while maintaining therapeutic efficiency. We examined the ability of a single injection of pegfilgrastim to significantly improve neutrophil recovery following autologous bone marrow transplantation (AuBMT) in rhesus macaques. On day 1, postmyeloablation (920 cGy x-irradiation) and AuBMT, animals received either 0.1% autologous serum for 18 consecutive days (n=13), or single doses of pegfilgrastim via the subcutaneous (s.c.) or intravenous (i.v.) route (300 or 100 micro g/kg), or a single dose of filgrastim at 300 micro g/kg via the s.c. or i.v. route, or filgrastim at 10 micro g/kg via the s.c. route (n=4) on a daily basis (range=days 12-17). Pharmacokinetic parameters and neutrophil recovery were assessed. A single dose of pegfilgrastim via the i.v. or s.c. route was as effective as daily filgrastim administration, resulting in significant improvement of neutrophil recovery after myeloablation and ABuMT. Effective pegfilgrastim plasma concentrations were maintained in neutropenic animals until after the onset of hematopoietic recovery. Enhanced pharmacokinetics in AuBMT cohorts are consistent with self-regulating, neutrophil-mediated clearance.