Limits...
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

Pegfilgrastim has enhanced in vivo activity relative to filgrastim. a Splenectomized mice were treated with a single injection of carrier, filgrastim, or pegfilgrastim and the absolute neutrophil count (ANC) was measured daily. Each timepoint represents 5–10 mice. b A single injection of pegfilgrastim is as effective as daily injections of filgrastim at restoring a normal neutrophil count in mice with chemotherapy-induced neutropenia. Neutropenia was induced in mice using a single intravenous injection of 5-fluorouracil 150 mg/kg on day 0. Mice were then randomized (n = 40 mice/group) and treated with carrier, daily injections of filgrastim 300 µg/kg (days 2–11), or a single injection of pegfilgrastim 1000 µg/kg on day 2. Daily ANC values were derived using four mice/group. Reproduced from Molineux et al. [78] with permission from Elsevier (© 1999 International Society for Experimental Hematology)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4488452&req=5

Fig3: Pegfilgrastim has enhanced in vivo activity relative to filgrastim. a Splenectomized mice were treated with a single injection of carrier, filgrastim, or pegfilgrastim and the absolute neutrophil count (ANC) was measured daily. Each timepoint represents 5–10 mice. b A single injection of pegfilgrastim is as effective as daily injections of filgrastim at restoring a normal neutrophil count in mice with chemotherapy-induced neutropenia. Neutropenia was induced in mice using a single intravenous injection of 5-fluorouracil 150 mg/kg on day 0. Mice were then randomized (n = 40 mice/group) and treated with carrier, daily injections of filgrastim 300 µg/kg (days 2–11), or a single injection of pegfilgrastim 1000 µg/kg on day 2. Daily ANC values were derived using four mice/group. Reproduced from Molineux et al. [78] with permission from Elsevier (© 1999 International Society for Experimental Hematology)

Mentions: The in vivo activity of pegfilgrastim compared to filgrastim was evaluated in both normal and neutropenic mice by subcutaneous (SC) injection. ANC is commonly used as a pharmacodynamic marker because it is straightforward to measure and represents the target cell for eliciting clinical benefit in neutropenic patients. In normal mice a single dose of pegfilgrastim (1000 µg/kg SC) increased the ANC for 5 days, whereas a single injection of filgrastim at a higher dose (2500 µg/kg SC) increased the ANC for only 1–2 days (Fig. 3a). In a model of chemotherapy-induced neutropenia, control mice that received neither filgrastim nor pegfilgrastim experienced 7 days of neutropenia, whereas mice treated with either daily filgrastim (300 µg/kg SC, days 2–11) or a single dose of pegfilgrastim (1000 µg/kg SC) experienced only 2 days of neutropenia (Fig. 3b). These data demonstrated that a single injection of pegfilgrastim was as effective in stimulating neutrophil recovery as multiple daily injections of filgrastim.Fig. 3


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

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

Pegfilgrastim has enhanced in vivo activity relative to filgrastim. a Splenectomized mice were treated with a single injection of carrier, filgrastim, or pegfilgrastim and the absolute neutrophil count (ANC) was measured daily. Each timepoint represents 5–10 mice. b A single injection of pegfilgrastim is as effective as daily injections of filgrastim at restoring a normal neutrophil count in mice with chemotherapy-induced neutropenia. Neutropenia was induced in mice using a single intravenous injection of 5-fluorouracil 150 mg/kg on day 0. Mice were then randomized (n = 40 mice/group) and treated with carrier, daily injections of filgrastim 300 µg/kg (days 2–11), or a single injection of pegfilgrastim 1000 µg/kg on day 2. Daily ANC values were derived using four mice/group. Reproduced from Molineux et al. [78] with permission from Elsevier (© 1999 International Society for Experimental Hematology)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Pegfilgrastim has enhanced in vivo activity relative to filgrastim. a Splenectomized mice were treated with a single injection of carrier, filgrastim, or pegfilgrastim and the absolute neutrophil count (ANC) was measured daily. Each timepoint represents 5–10 mice. b A single injection of pegfilgrastim is as effective as daily injections of filgrastim at restoring a normal neutrophil count in mice with chemotherapy-induced neutropenia. Neutropenia was induced in mice using a single intravenous injection of 5-fluorouracil 150 mg/kg on day 0. Mice were then randomized (n = 40 mice/group) and treated with carrier, daily injections of filgrastim 300 µg/kg (days 2–11), or a single injection of pegfilgrastim 1000 µg/kg on day 2. Daily ANC values were derived using four mice/group. Reproduced from Molineux et al. [78] with permission from Elsevier (© 1999 International Society for Experimental Hematology)
Mentions: The in vivo activity of pegfilgrastim compared to filgrastim was evaluated in both normal and neutropenic mice by subcutaneous (SC) injection. ANC is commonly used as a pharmacodynamic marker because it is straightforward to measure and represents the target cell for eliciting clinical benefit in neutropenic patients. In normal mice a single dose of pegfilgrastim (1000 µg/kg SC) increased the ANC for 5 days, whereas a single injection of filgrastim at a higher dose (2500 µg/kg SC) increased the ANC for only 1–2 days (Fig. 3a). In a model of chemotherapy-induced neutropenia, control mice that received neither filgrastim nor pegfilgrastim experienced 7 days of neutropenia, whereas mice treated with either daily filgrastim (300 µg/kg SC, days 2–11) or a single dose of pegfilgrastim (1000 µg/kg SC) experienced only 2 days of neutropenia (Fig. 3b). These data demonstrated that a single injection of pegfilgrastim was as effective in stimulating neutrophil recovery as multiple daily injections of filgrastim.Fig. 3

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