Update on Pegfilgrastim (Neulasta)

By John Zoidis, MD
Published: Tuesday, Jun 08, 2010
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Pegfilgrastim (Neulasta) is a covalent conjugate of recombinant methionyl human granulocyte colony-stimulating factor (G-CSF; filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble, 175–amino acid protein with a molecular weight of approximately 19 kD. Filgrastim is obtained from the bacterial fermentation of a strain of Escherichia coli transformed with a genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim, a 20-kD monomethoxypolyethylene glycol molecule is covalently bound to the n-terminal methionyl residue of filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD.

Pegfilgrastim is a longer-acting form of filgrastim (Neupogen), Amgen’s original leukocyte- stimulating agent. Pegfilgrastim requires only one injection per chemotherapy cycle, while filgrastim may require daily injections for up to 14 days following chemotherapy.

Both filgrastim and pegfilgrastim are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end-cell functional activation. Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo, compared with filgrastim.

Indication

Pegfilgrastim was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) in 2002 for reducing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Pharmacology

Dr. Ziad Atassi, University of Ulm, Ulm, Germany and colleagues evaluated the pharmacokinetics, safety, and efficacy of pegfilgrastim in 22 female patients with axillary metastatic breast cancer. Subjects received dose-dense chemotherapy consisting of 3x4 sequential single-drug cycles of epirubicin 90 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2 on a q15d schedule. Pegfilgrastim was administered 24 hours after chemotherapy. Blood samples for pharmacokinetic studies were taken on days 8, 10, and 12 of each cycle. The mean pegfilgrastim serum level on day 1 of each cycle was 2.88 ng/mL, 1.66 ng/mL, and 0.51 ng/mL on days 1, 10, and 12 of each cycle, respectively. The minimum value was observed on day 12 of cycle 5. Pegfilgrastim remained bioavailable until day 12 of each cycle with absent cumulative effects. Four patients presented with a single grade 3 neutropenia event, and no cases of febrile neutropenia were noted at any cycle. Nine events of >grade 1 bone pain were noted. Considering the low adverse event rate, the investigators suggested that dose-dense chemotherapy with primary pegfilgrastim prophylaxis is a safe option for high-risk breast cancer patients.

Pegfilgrastim for the Treatment of Chemotherapy- Associated Myelosuppression in

Pediatric Patients with Solid Tumors


Dr. Jessica A. Pollard and colleagues at the Fred Hutchinson Cancer Research Center, Seattle, Washington, reported their institutional experience with pegfilgrastim following doseintensive chemotherapy for solid tumors. Thirty-nine pediatric patients were included in this retrospective review. The median age of patients evaluated was 12 years (range, 0.17–23 yr) and the median weight was 50 kg (range, 4–107 kg). Primary diagnoses included osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, soft tissue sarcoma, neuroblastoma, Hodgkin’s disease, and other solid tumors. A total of 141 chemotherapy courses with pegfilgrastim support were administered (median, 4 courses per patient). No adverse events related to pegfilgrastim were noted. Severe neutropenia occurred in 46% of courses. Overall, the median duration of severe neutropenia was 0 days (range, 0-8 days). Febrile neutropenia occurred in 28% of courses. Of particular interest were eight patients treated with interval-compressed (every 14 days) sarcoma chemotherapy. Of 51 courses administered, the median course duration was 15 days (range, 14–28 days). The investigators concluded that pegfilgrastim administration following dose intensive chemotherapy for solid tumors is safe and feasible in children, including those <45 kg. They noted that the frequency and duration of severe neutropenia, as well as the incidence of febrile neutropenia, were similar to historic data on filgrastim.

GROC plus Pegfilgrastim in Relapsed Aggressive Non-Hodgkin’s Lymphoma


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