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Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor.

Arvedson T, O'Kelly J, Yang BB - BioDrugs (2015)

Bottom Line: Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim.Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy.This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim.

View Article: PubMed Central - PubMed

Affiliation: Amgen Inc., 14-1-B, One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA, tara.arvedson@amgen.com.

ABSTRACT
Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.

No MeSH data available.


Related in: MedlinePlus

Serum pegfilgrastim concentrations and absolute neutrophil count (ANC) profile in breast cancer patients treated with doxorubicin (60 mg/m2), docetaxel (75 mg/m2), and a single administration of pegfilgrastim (100 µg/kg). Reproduced from Holmes et al. [14] with permission of Wiley Materials (© 2008 American College of Clinical Pharmacology)
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Fig5: Serum pegfilgrastim concentrations and absolute neutrophil count (ANC) profile in breast cancer patients treated with doxorubicin (60 mg/m2), docetaxel (75 mg/m2), and a single administration of pegfilgrastim (100 µg/kg). Reproduced from Holmes et al. [14] with permission of Wiley Materials (© 2008 American College of Clinical Pharmacology)

Mentions: Another consequence of the G-CSF-R/pegfilgrastim interaction is the stimulation of neutrophil precursor proliferation and differentiation. Figure 5 demonstrates the relationship between pegfilgrastim serum concentrations and circulating neutrophils in breast cancer patients treated with doxorubicin (60 mg/m2) and docetaxel (75 mg/m2), followed by a single injection of pegfilgrastim (100 µg/kg) 1 day later [14]. After SC administration of pegfilgrastim, serum concentrations of pegfilgrastim were sustained during neutropenia. ANC levels started to increase after the nadir on day 7, resulting in a rapid decline of serum concentrations of pegfilgrastim due to neutrophil-mediated clearance. Thus, during chemotherapy-induced neutropenia, circulating pegfilgrastim concentrations remain elevated until there is an increase in the ANC, which leads to increased pegfilgrastim consumption and self-regulated clearance. In comparison, serum concentrations of filgrastim were rapidly cleared after each injection, and multiple daily injections of filgrastim were required to maintain its clinical efficacy [14]. A semi-mechanistic model that includes neutrophil-mediated clearance adequately describes the relationship between pegfilgrastim serum concentrations and the ANC profile in healthy subjects [53] and in patients with non-small-cell lung cancer [54].Fig. 5


Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor.

Arvedson T, O'Kelly J, Yang BB - BioDrugs (2015)

Serum pegfilgrastim concentrations and absolute neutrophil count (ANC) profile in breast cancer patients treated with doxorubicin (60 mg/m2), docetaxel (75 mg/m2), and a single administration of pegfilgrastim (100 µg/kg). Reproduced from Holmes et al. [14] with permission of Wiley Materials (© 2008 American College of Clinical Pharmacology)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4488452&req=5

Fig5: Serum pegfilgrastim concentrations and absolute neutrophil count (ANC) profile in breast cancer patients treated with doxorubicin (60 mg/m2), docetaxel (75 mg/m2), and a single administration of pegfilgrastim (100 µg/kg). Reproduced from Holmes et al. [14] with permission of Wiley Materials (© 2008 American College of Clinical Pharmacology)
Mentions: Another consequence of the G-CSF-R/pegfilgrastim interaction is the stimulation of neutrophil precursor proliferation and differentiation. Figure 5 demonstrates the relationship between pegfilgrastim serum concentrations and circulating neutrophils in breast cancer patients treated with doxorubicin (60 mg/m2) and docetaxel (75 mg/m2), followed by a single injection of pegfilgrastim (100 µg/kg) 1 day later [14]. After SC administration of pegfilgrastim, serum concentrations of pegfilgrastim were sustained during neutropenia. ANC levels started to increase after the nadir on day 7, resulting in a rapid decline of serum concentrations of pegfilgrastim due to neutrophil-mediated clearance. Thus, during chemotherapy-induced neutropenia, circulating pegfilgrastim concentrations remain elevated until there is an increase in the ANC, which leads to increased pegfilgrastim consumption and self-regulated clearance. In comparison, serum concentrations of filgrastim were rapidly cleared after each injection, and multiple daily injections of filgrastim were required to maintain its clinical efficacy [14]. A semi-mechanistic model that includes neutrophil-mediated clearance adequately describes the relationship between pegfilgrastim serum concentrations and the ANC profile in healthy subjects [53] and in patients with non-small-cell lung cancer [54].Fig. 5

Bottom Line: Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim.Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy.This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim.

View Article: PubMed Central - PubMed

Affiliation: Amgen Inc., 14-1-B, One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA, tara.arvedson@amgen.com.

ABSTRACT
Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.

No MeSH data available.


Related in: MedlinePlus