Pegfilgrastim Biosimilars: Where Are We Now?

In 1991, the U.S. Food & Drug Administration (FDA) approved rmetHuG-CSF for human use. This recombinant methionyl human granulocyte colony-stimulating factor, or filgrastim, saw use in over 1 million patients in its first 5 years on the market. In 2002, the FDA approved a version of filgrastim with covalent linkage to a monomethoxypolyethylene glycol, increasing the molecular size and half-life to replace multiple days of dosing with a single injection. These medications remained standard of care for neutropenia until the Biologics Price Competition and Innovation Act of 2009 created an abbreviated pathway to licensure for biologic products. Practitioners now have their pick of numerous and expanding options for pegfilgrastim biosimilars.

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Once Per Cycle Pegfilgrastim Versus Daily Filgrastim in Pediatric Patients with Ewing Sarcoma.

Blood ◽

10.1182/blood.v104.11.2919.2919 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2919-2919

Author(s):

Gerald Wendelin ◽

Herwig Lackner ◽

Wolfgang Schwinger ◽

Petra Sovinz ◽

Christian Urban

Keyword(s):

Ewing Sarcoma ◽

Pediatric Patients ◽

Actinomycin D ◽

Single Injection ◽

Severe Neutropenia ◽

Granulocyte Colony Stimulating Factor ◽

Subcutaneous Injections ◽

Comparable Effect ◽

Chemotherapy Patients ◽

Stimulating Factor

Abstract The administration of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) Filgrastim for reducing the duration of severe neutropenia after cytotoxic chemotherapy has become an important part of oncologic supportive care. Due to the short serum half-life Filgrastim has to be administrated daily by subcutaneous injections. Frequent injections however mark a problem in pediatric patients. Studies in adult patients have shown a comparable effect of the new long lasting rhG-CSF Pegfilgrastim which has to be administrated only once per cycle. In the current study the effects of Pegfilgrastim in pediatric patients were analysed. Five patients (10–16 years) with Ewing sarcoma were treated in a cross over study design alternately with Pegfilgrastim and Filgrastim following the EURO E.W.I.N.G. 99 protocol. Starting on day 4 after chemotherapy patients received Filgrastim 10μg/kg daily by subcutaneous injection until an absolute neutrophil count (ANC) >1000/μl after the expected nadir. Pegfilgrastim 100μg/kg was administrated on day 4 once per cycle subcutaneously. In 3 patients the stimulation with rhG-CSF was performed after each of the 6 preoperative VIDE-(Vincristin, Ifosfamide, Doxorubicin, Etoposide) cycles, in 2 patients after 8 postoperative VAI-(Vincristin, Actinomycin D, Ifosfamide), and in 2 patients after 7 postoperative VAC-(Vincristin, Actinomycin D, Cyclophosphamide) cycles of the EURO-E.W.I.N.G. 99 protocol. The duration of grade 4 neutropenia after single administration of Pegfilgrastim was 2,8 ±3,1 (0–10) days, after daily administration of Filgrastim 3,1 ± 2,7 (0–8) days. The number of days with a body temperature over 38 degrees and grade 4 neutropenia at the same time was 0,9 ±1,5 (0–6) after Pegfilgrastim and 0,9± 1,4 (0–4) after Filgrastim. Filgrastim had to be injected 6,7 ± 1,8 (3–10) times per cycle. Bone pain associated with Pegfilgrastim was noted in only one patient. Costs for Pegfilgrastim were 16% lower than for Filgrastim. We conclude that in pediatric patients with Ewing sarcoma the duration of severe neutropenia and number of days with febrile neutropenia after once per cycle Pegfilgrastim and daily Filgrastim are comparable. By using Pegfilgrastim the number of subcutaneous injections can be reduced to one single injection and costs can be lowered.

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Effects of a Single Injection of Recombinant Human Granulocyte Colony-stimulating Factor on Bone in Rats.

Journal of Toxicologic Pathology ◽

10.1293/tox.11.159 ◽

1998 ◽

Vol 11 (3) ◽

pp. 159-162 ◽

Cited By ~ 2

Author(s):

Masami Suzuki ◽

Kenji Adachi ◽

Tetsuro Sugimoto ◽

Hiroyuki Nakayama ◽

Kunio Doi

Keyword(s):

Single Injection ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

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Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis

Seminars in Liver Disease ◽

10.1055/s-0040-1719177 ◽

2021 ◽

Author(s):

Chandan Kumar Kedarisetty ◽

Anupam Kumar ◽

Shiv Kumar Sarin

Keyword(s):

Alcoholic Hepatitis ◽

Severe Disease ◽

Unmet Need ◽

Standard Of Care ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Term Survival ◽

Dose Monitoring ◽

Severe Alcoholic Hepatitis ◽

Stimulating Factor

AbstractAlcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.

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G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Blood ◽

10.1182/blood-2010-09-308387 ◽

2011 ◽

Vol 117 (16) ◽

pp. 4349-4357 ◽

Cited By ~ 114

Author(s):

Anja Köhler ◽

Katia De Filippo ◽

Mike Hasenberg ◽

Cindy van den Brandt ◽

Emma Nye ◽

...

Keyword(s):

Bone Marrow ◽

Single Injection ◽

Neutrophil Granulocytes ◽

Clinical Grade ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Short Term ◽

Stimulating Factor

Abstract Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker.

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A SINGLE INJECTION OF POLYETHYLENE-GLYCOL GRANULOCYTE COLONY-STIMULATING FACTOR STRONGLY PROLONGS SURVIVAL OF MICE WITH SYSTEMIC CANDIDIASIS

Cytokine ◽

10.1006/cyto.1999.0670 ◽

2000 ◽

Vol 12 (6) ◽

pp. 666-670 ◽

Cited By ~ 14

Author(s):

Annemiek B van Spriel ◽

Ingrid E van den Herik-Oudijk ◽

Jan G.J van de Winkel

Keyword(s):

Polyethylene Glycol ◽

Single Injection ◽

Systemic Candidiasis ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

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White Blood Cell Changes Following Treatment with a Combination of Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) and Intravenous Immunoglobulin (IVIG) in Necrotizing Enterocolitis (NEC)

Journal of Pediatric Infectious Diseases ◽

10.1055/s-0037-1603331 ◽

2017 ◽

Vol 12 (03) ◽

pp. 184-192

Author(s):

Prabhakar Kocherlakota ◽

Sri Narayana ◽

Jonathan Blau ◽

Edmund La Gamma

Keyword(s):

Blood Cell ◽

Intravenous Immunoglobulin ◽

Standard Of Care ◽

Treated Group ◽

Standard Group ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Elbw Neonates ◽

Wbc Count ◽

Stimulating Factor

Objective We sought to determine whether recombinant human granulocyte colony stimulating factor (rhG-CSF) and intravenous immunoglobulin (IVIG) combination can increase white blood cell (WBC) count and improve the survival of extremely low-birth-weight (ELBW) neonates having necrotizing enterocolitis (NEC) with Bell stage II or above. Methods This retrospective chart review consisted of ELBW neonates with NEC provided with standard of care (standard group) or standard of care and a combination of rhG-CSF along with IVIG (treated group) at the discretion of the treating physician. Serial blood counts (days 0,1,2,3, and 7 to 10), survival, need for surgical intervention, time to reach full feeds, and time to discharge were compared between the two groups. Results The treated (27 neonates) and the standard (35 neonates) groups had birth weights of 857 ± 52 g and 1,009 ± 50 g; gestational ages of 26 ± 0.5 and 28 ± 0.5 weeks; WBC counts of 7,950 ± 6,452 and 14,105 ± 9,578/mm3; absolute neutrophil count (ANC) of 3,930 ± 5,152 and 7,117 ± 7,545/mm3, respectively (p < 0.05). During the study, WBC count and ANC increased in the treated group till days 7 to 10, but decreased till day 3 in the standard group (p < 0.05). ANC (11-fold) and monocytes (4-fold) increased in the treated patients with neutropenia by days 7 to 10 (p < 0.05). There was no change in the survival, need for surgery, time to reach full feed, or time to discharge between the two groups. Conclusion The combination of rhG-CSF and IVIG increased WBC, ANC, and monocytes in the treated group but did not affect the survival, need for surgery, time to reach full feed, or time to discharge.

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