Peg-Alvograstim Mechanism of Action

Pharmacotherapeutic Group: Cytokines. ATC Code: L03AA13.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic effects: Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule.
Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance.
Pegfilgrastim and filgrastim have been shown to have identical modes of action causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function.
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro.
Pharmacokinetics: Distribution: After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy.
Elimination: The elimination of pegfilgrastim is non-linear with respect to dose, serum clearance of pegfilgrastim decreases with increasing dose.
Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure).
Due to neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. In an open-label, single dose study (n=31) various stages of renal impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim.
Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (>65 years) is similar to that in adults.

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Toxicology: Preclinical Safety Data: Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and splenic enlargement.
There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo-loss) at low subcutaneous doses. In rat studies, it was shown that pegfilgrastim may cross the placenta.
The relevance of these findings for humans is not known.