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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Cytokines also exert many adverse effects during their exploitation as therapeutics due to their inherent properties such as pleotropic, short serum half-life. Cytokines are pleotropic which implies that they act on more than one cell type causing conflicting effects. Hence, there is a need to engineer cytokines with high specificity, and extended half-life. One of the strategies employed to increase the half-life of therapeutic cytokines is PEGylation. This involves conjugation of PEG chains to cytokine/chemokine either enzymatically or chemically. It prolongs the life of cytokines by preventing them from proteases and by increasing their hydrodynamic size (Harris and Chess, 2003; Jevsevar et al., 2010). PEG-G-CSF (pegfilgrastim) is PEGylated colony stimulating factor which has been approved for the treatment of neutropenia (Crawford, 2003). Two PEGylated cytokines IFN-α-2a (Pegasys®) and IFN-α-2b (Pegintron®) are employed for treating chronic hepatitis C (Perry and Jarvis, 2001; Bukowski et al., 2002).
General Management of Blood Cancers
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
The present generation of G-CSF has a short half-life and daily administration, for up to 14 days, is often required. Such frequent injections may dissuade some patients from adherence and increases the burden on healthcare providers. Many efforts have, therefore, been directed to improve on this and one such effort has resulted in the development of a novel molecule, pegfilgrastim (Neulasta). Pegfilgrastim is a sustained duration, pegylated form of G-CSF (filgrastim; Neupogen) that should have the same clinical benefits as filgrastim but require less frequent dosing. Unlike filgrastim, which is primarily excreted via the kidneys, pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors. This “self-regulating” clearance mechanism results in sustained serum levels of pegfilgrastim for as long as it takes to achieve neutrophil recovery. Hence, pegfilgrastim only requires to be administered once every 21 days. Toxicity analysis confirms that pegfilgrastim can be administered safely; mild-to-moderate bone pain appears to be the only significant adverse event reported so far. Notably, pegfilgrastim was recently approved by the European Medicines Evaluation Agency for the treatment of neutropenia associated with cytotoxic chemotherapy for selected cancers.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
Primary prophylaxis involves the use of a G-CSF beginning in the first cycle of treatment. For "dose-dense" regimens, G-CSFs are required. Clinical trial data support the use of G-CSF when the risk of neutropenic fever is ≥20%. Adjuvant treatment of early-stage breast cancer with TAC or FEC100 or the use of CHOP in older patients with aggressive non-Hodgkin's lymphoma are examples. G-CSF should be given 24-72 hours after the administration of chemotherapy and should be continued until an ANC of at least 2 to 3×103 cells/ μLmm3. In adults, the recommended G-CSF dose is 5μg/kg/ day for filgrastim. For a longer-acting G-CSF, a single injection of pegfilgrastim 6mg (a lower dose was shown to be as effective in certain populations), given 1-3 days after administration of chemotherapy, is sufficient per chemotherapy cycle. Â 7,8 A recent study showed that less frequent G-CSF dosing is as effective as daily G-CSF and is associated with less bone pain. Â 9 However, since this finding is for patients in whom G-CSF is not routinely indicated, the efficacy of less frequent G-CSF dosing has not been definitively proven.
Cost-efficiency and expanded access of prophylaxis for chemotherapy-induced (febrile) neutropenia: economic simulation analysis for the US of conversion from reference pegfilgrastim to biosimilar pegfilgrastim-cbqv
Published in Journal of Medical Economics, 2020
Karen MacDonald, Ali McBride, Neda Alrawashdh, Ivo Abraham
Comparative analytics demonstrated that pegfilgrastim-cbqv has a high degree of similarity in structure, pegylation, strength, potency, receptor binding, purity, and stability to its reference, pegfilgrastim19–21. In the clinical development phase, all pharmacodynamic and pharmacokinetic endpoints were met19,22. Immunogenicity was assessed in all studies but was the primary focus of one study that found no clinically meaningful treatment-emergent neutralizing antibodies19,20. Safety outcomes across all studies were similar to those for pegfilgrastim, with bone pain and pain in the extremities being the most common adverse reactions22,23. Pegfilgrastim-cbqv was approved by the Food and Drug Administration in November 2018 via the Biologics License Application pathway23.
Prophylaxis of febrile neutropenia with colony-stimulating factors: the first 25 years
Published in Current Medical Research and Opinion, 2020
John Edelsberg, Derek Weycker, Mark Bensink, Charles Bowers, Gary H. Lyman
Among observational studies with data on at least 500 cycles, the results have been mixed, with two studies reporting little or no difference in rates of grade 4 neutropenia and FN60,62 and two reporting significant differences in FN risk favoring delayed pegfilgrastim59,63. In the largest of these four studies (179,000 cycles), only patients receiving intermediate- or high-risk regimens were included and adjustment was made for differences in FN risk factors between the two groups59. The risk of FN was higher in all cycles for patients receiving same-day pegfilgrastim, odds ratio (OR), 1.5 (95% CI 1.3–1.6). Similar findings were reported in follow-up studies using private healthcare claims data spanning 2010–2015 (OR = 1.3, 95% CI 1.2–1.4) and using Medicare claims data (OR = 1.3, 95% CI 1.2–1.4)64,65. A recent systematic review of the literature on this topic concluded that the literature supports “administration of pegfilgrastim to patients at least 1 d after the completion of a chemotherapy cycle”66.
Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates
Published in International Journal of Radiation Biology, 2020
Karen Wong, Polly Y. Chang, Mark Fielden, Anne Marie Downey, Deborah Bunin, James Bakke, Janet Gahagen, Lalitha Iyer, Sameer Doshi, Wieslaw Wierzbicki, Simon Authier
Romiplostim (NPLATE®2018) and pegfilgrastim (NEULASTA®2018) were provided by Amgen Inc. (Thousand Oaks, CA, USA). Prior to administration, romiplostim was reconstituted with sterile water for injection to a concentration of 0.5 mg/mL. Starting at 24 h post-irradiation, animals received either saline (vehicle control), romiplostim only, pegfilgrastim only or both romiplostim and pegfilgrastim as outlined in Table 1. Romiplostim and vehicle doses were divided and administered by subcutaneous (SC) injection over six sites on the upper back and/or lumbar area. Pegfilgrastim was administered by SC injection at a separate seventh site on the upper back. The volume administered to each animal was calculated and adjusted based on body weight. To decrease variability from the effect of differing fluid volumes on the status of the animals, all animals received sterile saline for injection (control animals) or romiplostim (2.5 or 5 mg/kg) at 10 mL/kg. No additional fluids were administered to control animals to adjust for the dose volume of pegfilgrastim (0.03 mg/kg) as the volume was considered minimal.