Neutrophil-mediated clearance

Pegfilgrastim plasma concentrations were modeled using a two-compartment model with a delayed, first-order absorption process. The clearance of pegfilgrastim was described by parallel linear and neutrophil-mediated clearance pathways ... 

The neutrophil-mediated clearance was expressed as a Michaelis-Menten function, because G-CSF receptor binding is subject to saturation. The product of kcat and the ratio of ANC and ANC at baseline is the maximum velocity of drug elimination from this pathway, km is the Michaelis constant, and C is the pegfilgrastim concentration. CL2 denotes the linear clearance pathway. 

Nedocromil was developed as a result of research for compounds to control asthma. Its activity has been studied in vitro in a variety of inflammatory cells, including mast cells, eosinophils, and polymorphonuclear leukocytes. Nedocromil appears to be more potent than cromolyn in its ability to inhibit immimologic release of mast cell mediators. It can also modify the actions of eosinophils, neutrophils, monocytes, macrophages, and platelets. Pharmacokinetic studies indicate that ocular penetration of nedocromil is slow, and clearance from the eye is relatively rapid. Nedocromil differs from the other mast cell stabilizers in that it is effective within 15 to 30 minutes. 

Finally, clearance may change over time for macromolecules whose clearance is mediated by cell surface receptors and, in the case of mABs, antigens. This is illustrated by an experiment in three patients with metastatic breast cancer who received G-CSF for two consecutive days as a continuous infusion (45). Absolute neutrophil counts were obtained every morning and there was a very strong positive correlation between neutrophil count and G-CSF clearance (Figure 32.12). Clearance on day 2 was 4.6 mL/hr/kg, increasing to 8.3 mL/hr/kg on day 9. Thus, neutrophil production may mediate the clearance of G-CSF. 

Chapter 3) produced by recombinant means in E. coli. It regulates the production of neutrophils and is indicated for the treatment of neutropenia associated with various medical conditions. Neulasta is a PEGylated form filgrastim, also used to treat neutropenia. It exhibits an extended duration of action, due to the PEG-mediated reduction in product renal clearance rate. 

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