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Anti-cancer Drugs Apr 2003Pegylation of a protein can improve not only its formulation properties, but also both its pharmacokinetic and pharmacodynamic performance. Pegfilgrastim was made by... (Comparative Study)
Comparative Study Review
Pegylation of a protein can improve not only its formulation properties, but also both its pharmacokinetic and pharmacodynamic performance. Pegfilgrastim was made by linking a 20-kDa polyethylene glycol molecule to filgrastim, producing a long-acting cytokine requiring less frequent dosing than its parent drug. This review describes the clinical development of pegfilgrastim, and discusses its potential benefits to patients and caregivers in the prophylaxis of chemotherapy-induced neutropenia. Pegfilgrastim has a longer half-life and slower elimination rate than filgrastim, resulting in an increased serum concentration over time. Serum levels of pegfilgrastim are maintained until after a chemotherapy-induced neutrophil nadir and then decline rapidly as the neutrophil count recovers, consistent with a neutrophil-mediated clearance mechanism. In two pivotal phase III studies of women receiving chemotherapy for breast cancer, a single injection of pegfilgrastim per chemotherapy cycle, dosed either by body weight (100 microg/kg) or as a fixed dose (6 mg), was comparable to daily filgrastim (5 microg/kg) for all efficacy parameters, including duration of severe neutropenia and depth of neutrophil nadir. Analysis of pooled data from these studies showed a significantly lower incidence of febrile neutropenia in patients receiving pegfilgrastim compared with filgrastim (11 versus 19%, p<0.05), and a trend towards a lower risk of hospitalization and use of i.v. anti-infectives. The safety profiles of pegfilgrastim and filgrastim were similar. Pegfilgrastim given once per chemotherapy cycle is as effective and well tolerated as daily injections of filgrastim. With its more convenient dosing regimen, pegfilgrastim has the potential to improve quality of life and compliance in patients, and to be more cost effective.
Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hodgkin Disease; Humans; Injections, Subcutaneous; Lung Neoplasms; Lymphoma, Non-Hodgkin; Neutropenia; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins
PubMed: 12679729
DOI: 10.1097/00001813-200304000-00002 -
Advanced Drug Delivery Reviews Jan 2008Neulasta (pegfilgrastim) is a PEGylated version of its parent molecule NEUPOGEN (Filgrastim). This work describes the formulation development for Neulasta... (Review)
Review
Neulasta (pegfilgrastim) is a PEGylated version of its parent molecule NEUPOGEN (Filgrastim). This work describes the formulation development for Neulasta (pegfilgrastim), and the analytical techniques used to monitor degradation during these studies. Stability was assessed as a function of pH, protein concentration, buffer type, tonicity modifiers and surfactant concentration under both accelerated conditions and quiescent long-term storage. The stability of Neulasta (pegfilgrastim) to agitation and successive freeze-thaw cycles was also assessed. Neulasta (pegfilgrastim), at a protein concentration of 10 mg/mL formulated in 10 mM acetate, pH 4.0 with 5% sorbitol and 0.004% polysorbate 20, is stable for two years stored at 2-8 degrees C.
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Drug Stability; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Hydrogen-Ion Concentration; Polyethylene Glycols; Recombinant Proteins; Technology, Pharmaceutical
PubMed: 17822802
DOI: 10.1016/j.addr.2007.04.017 -
Expert Opinion on Biological Therapy Dec 2005Granulocyte colony-stimulating factors such as filgrastim (Neupogen, Amgen, Inc.) and pegfilgrastim (Neulasta, Amgen, Inc.) are frequently used in clinical practice for... (Review)
Review
Granulocyte colony-stimulating factors such as filgrastim (Neupogen, Amgen, Inc.) and pegfilgrastim (Neulasta, Amgen, Inc.) are frequently used in clinical practice for the prevention of chemotherapy-induced neutropenia and its potentially life-threatening complications. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have shown that a single, fixed subcutaneous dose of pegfilgrastim 6 mg is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Postregistrational trials have been conducted to evaluate the use of pegfilgrastim with emerging dose-dense regimens, in myeloid cancers and for mobilisation and engraftment of autologous stem cells. Ongoing clinical trials continue to explore further potential uses for pegfilgrastim.
Topics: Animals; Delayed-Action Preparations; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins
PubMed: 16318427
DOI: 10.1517/14712598.5.12.1635 -
Bone Marrow Transplantation Apr 2015Trial outcomes comparing cytokine agents for PBSC mobilization in autologous hematopoietic transplant patients have been controversial. We performed a systematic review... (Comparative Study)
Comparative Study Meta-Analysis Review
Trial outcomes comparing cytokine agents for PBSC mobilization in autologous hematopoietic transplant patients have been controversial. We performed a systematic review and meta-analysis of evidence available on pegfilgrastim vs filgrastim in chemo-cytokine mobilization. Electronic literature searches of PubMed, EMBASE and CENTRAL identified nine articles eligible for qualitative analysis with one randomized controlled trial. Eight articles involving 719 patients were included in the meta-analysis. Results showed similar CD34+ cell collection yields for pegfilgrastim and filgrastim (SDM -0.08, 95% CI: -0.388 to 0.228). On comparison with filgrastim, pegfilgrastim showed a significantly earlier apheresis onset time (SDM: -0.512, 95% CI: -0.973 to -0.050) and reduction in required apheresis procedures (SDM -0.260, 95% CI: -0.466 to -0.054). Times to leukocyte (⩾1.0 × 10(9)/L) and platelet (⩾20 × 10(9)/L) recovery were similar between groups (SDM: 0.015, 95% CI: -0.41 to 0.44 and SDM: 0.309, 95% CI: -0.11 to 0.72, respectively). Both agents were well tolerated and mild bone pain was the most frequently reported adverse event. Pegfilgrastim may be a convenient alternative to filgrastim in PBSC mobilization for multiple myeloma and lymphoma patients, but further studies are required to clarify effects of cytokine dosage and previous cytotoxic exposure in specific subpopulations.
Topics: Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematologic Agents; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Male; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Recombinant Proteins
PubMed: 25581410
DOI: 10.1038/bmt.2014.297 -
Pegfilgrastim: current and future perspectives in the treatment of chemotherapy-induced neutropenia.Future Oncology (London, England) Dec 2006Myeloid colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor) are commonly used in clinical... (Review)
Review
Myeloid colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor) are commonly used in clinical practice for the prevention of anticancer chemotherapy-induced neutropenia and its potentially life-threatening complications. Pegfilgrastim is a novel recombinant human G-CSF pharmaceutically developed by covalent binding of a polyethylene glycol molecule to the N-terminal sequence of filgrastim. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have demonstrated that a single, fixed, subcutaneous dose of pegfilgrastim is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Recent trials have been conducted to evaluate the use of pegfilgrastim in different clinical settings, including support of dose-dense regimens, mobilization and transplantation of hematopoietic stem cells.
Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins
PubMed: 17155894
DOI: 10.2217/14796694.2.6.667 -
Clinical Journal of Oncology Nursing 2003
Topics: Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Oncology Nursing; Patient Education as Topic; Polyethylene Glycols; Recombinant Proteins
PubMed: 12696226
DOI: 10.1188/03.CJON.238-241 -
The Annals of Pharmacotherapy Sep 2007To report a pediatric case of pegfilgrastim-induced hyperleukocytosis.
OBJECTIVE
To report a pediatric case of pegfilgrastim-induced hyperleukocytosis.
CASE SUMMARY
A 3-year-old boy with medulloblastoma therapy presented with white blood cell (WBC) count 0.1 x 10(3)/microL and absolute neutrophil count (ANC) 0.014 x 10(3)/microL on day 27 following a course of induction chemotherapy. The patient received pegfilgrastim 200 microg/kg the following day. On his return 6 days later for the next planned course of chemotherapy, hyperleukocytosis was determined, with WBC 149 x 10(3)/microL and ANC 110 x 10(3)/microL ("neutrophil overshoot"). No sources of the elevated WBC count other than administration of pegfilgrastim (eg, steroids, antiepileptics, infection) were present. Chemotherapy was delayed until the WBC count had fallen to 35.2 x 10(3)/microL (ANC 28.9 x 10(3)/microL). No sequelae from this adverse effect occurred.
DISCUSSION
Pegfilgrastim has unique saturable neutrophil receptor-mediated clearance, the ability for self-regulation. Due to this clearance mechanism, hyperleukocytosis associated with pegfilgrastim use is uncommon in adults and has not been previously reported in pediatrics. The pegfilgrastim dose in children is under investigation; however, 100-110 microg/kg has been effective and safe in this population. Use of the Naranjo probability scale suggested that pegfilgrastim was the probable cause of hyperleukocytosis in our patient.
CONCLUSIONS
Pegfilgrastim 200 microg/kg, in excess of the 100 microg/kg dose used in limited pediatric clinical trials, appeared to exceed saturable neutrophil receptor-mediated clearance. The inability of this mechanism to self-regulate neutrophil counts in the normal range led to neutrophil overshoot. Routine pediatric use of the pegylated dosage form of G-CSF should await further published clinical trials to validate a safe and effective dose.
Topics: Antineoplastic Agents; Cerebellar Neoplasms; Child, Preschool; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Leukocytes; Leukocytosis; Male; Medulloblastoma; Neutropenia; Polyethylene Glycols; Recombinant Proteins
PubMed: 17666580
DOI: 10.1345/aph.1K093 -
Clinical Transplantation 2012Granulocyte-colony-stimulating factors are helpful for the support of patients receiving autologous hematopoietic stem cell transplantation, resulting in faster... (Review)
Review
Granulocyte-colony-stimulating factors are helpful for the support of patients receiving autologous hematopoietic stem cell transplantation, resulting in faster neutrophil recovery and lower incidence of febrile neutropenia (FN). Our aim was to evaluate the use of pegfilgrastim vs. filgrastim with regard to absolute neutrophil count (ANC) recovery, risk, and duration of FN and length of hospital stay. Mean difference was the summary effect for continuous data, and odds ratio for binary data, using random-effects modeling. MEDLINE, EMBASE, and the Cochrane Registry of Randomized Controlled Trials were included in the search. Randomized controlled trials (RCTs), case-control studies, and studies with historical control group for filgrastim were eligible. Of the initial 114 studies screened, 12 studies were analyzed (four were RCTs, including one phase III trial). The use of pegfilgrastim resulted in a one d gain in ANC recovery (mean difference -0.82, 95% CI -1.07 to -0.57, p < 0.001) and duration of FN (-0.67, 95% CI -1.28 to -0.06, p < 0.001) but had no effect on the risk of FN or length of stay. Pegfilgrastim was more expensive (baseline marginal cost €116.97, p < 0.001), which was largely determined by the treatment duration and pegfilgrastim cost. Non-randomized setting attenuated the effect on duration of FN whereas delayed onset of filgrastim injections (to pegfilgrastim) overestimated the protective effect on the risk of FN. Both drugs are at least equally effective, though methodology and disease stratification in published trials warrant further improvement.
Topics: Animals; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Palliative Care; Polyethylene Glycols; Recombinant Proteins; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 22035044
DOI: 10.1111/j.1399-0012.2011.01532.x -
Current Medical Research and Opinion Jun 2022The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical,... (Review)
Review
OBJECTIVE
The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States.
METHODS
Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer.
RESULTS
No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic.
CONCLUSIONS
The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.
Topics: Adult; Biosimilar Pharmaceuticals; Filgrastim; Humans; Polyethylene Glycols; Therapeutic Equivalency; United States
PubMed: 35392751
DOI: 10.1080/03007995.2022.2061707 -
AJR. American Journal of Roentgenology Feb 2022
Topics: Filgrastim; Fluorodeoxyglucose F18; Humans; Polyethylene Glycols; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography
PubMed: 34549610
DOI: 10.2214/AJR.21.26821