Neocyte Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment and some end-cell functional activation.
Endogenous G-CSF is a lineage specific colony stimulating factor which is produced by monocytes, fibroblasts and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing, and the increased expression of some functions associated with cell surface antigens). G-CSF is not species specific and has been shown to have minimal direct in vivo and in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage.
Pharmacokinetics: Absorption and clearance of filgrastim follows first-order pharmacokinetic modeling without apparent concentration dependence. It is rapidly absorbed following subcutaneous (SC) injection, and peak serum concentrations are generally attained within 4 to 5 hours following rapid SC injection. SC administration of 3.45 mcg/kg body weight and 11.5 mcg/kg body weight resulted in maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours. Continuous intravenous (IV) infusion of 20 mcg/kg body weight of filgrastim over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL, respectively. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area under the concentration-time curves.
Filgrastim is rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver. The volume of distribution following a single IV or SC dose averaged 150 mL/kg body weight in both normal subjects and cancer patients. It is not known whether filgrastim is distributed into cerebrospinal fluid. It is also not known if the drug crosses the placenta or is distributed into milk.
The elimination half-life, in both normal subjects and cancer patients, was approximately 3.5 hours. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg body weight. Single parenteral doses or daily IV doses, over a 14-day period, resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes, following doses of 34.5 mcg/kg body weight) and for SC administration (210 minutes, following doses of 3.45 mcg/kg body weight). Continuous 24-hour IV infusions of 20 mcg/kg body weight over an 11- to 20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated.
Pharmacokinetics in special populations: Pediatric: The pharmacokinetics of filgrastim in pediatric patients after chemotherapy is similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim.
Geriatric: Pharmacokinetic data in geriatric patients (≥65 years old) are not available.
Renal or hepatic impairment: Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. Dose adjustment is not required in these circumstances. A trend toward higher systemic exposure to filgrastim is observed in patients with end-stage renal disease compared with healthy subjects and subjects with creatinine clearance of 30 to 60 mL/min.