The Design and Development of Pegfilgrastim (PEG-rmetHuG-CSF, Neulasta®)

Abstract

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.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…Unlike the polymer-protein conjugates, where the last FDA approval covered different diseases [126][127][128] such as hepatitis C [131], gout [132], acromegaly [133][134][135], neutropenia [136][137][138], Crohn's disease [139], renal anemia [140], and age-related macular degeneration [141][142][143], the research on polymer-drug conjugates has been focused on cancer treatment, with at least 20 conjugates currently in clinical trials (some of them in discontinued status) [127,130,144]. They are based on the traditional cytotoxic drugs (e.g.…”

PEGylation of therapeutic proteins

“…N-terminal PEGylation, performed as a reductive alkylation step with a PEG-aldehyde reagent and a reducing agent (e.g., sodium cianoborohydride) [44], was employed in the development of Neulasta® [45], which is an N-terminally mono-PEGylated G-CSF bearing a 20 kDa PEG, (EMEA product informationhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/neulasta/296102en6.pdf). The improved pharmacokinetic behavior enables administration only once per each chemotherapy cycle compared to the first generation, Neupogen®, which is administered daily (up to two weeks in each chemotherapy cycle).…”

Pegfilgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplant: phase II study

“…3 Pegylation of filgrastim leads to prolongation of half-life without loss of in vivo activity. [4][5][6] Pegfilgrastim (Neulasta s ; Amgen Inc., Thousand Oaks, CA, USA) has been approved by the Food and Drug Administration for prevention of chemotherapy-induced neutropenia after standard dose chemotherapy. However, the safety and efficacy of pegfilgrastim for neutrophil support following chemotherapy to patients undergoing HDC and ASCT is not known.…”