Pharmacokinetics and Pharmacodynamics of Pegfilgrastim

摘要: Pegfilgrastim is a sustained-duration form of filgrastim, recombinant methionyl human granulocyte colony-stimulating factor (G-CSF), to which 20 kDa polyethylene glycol molecule covalently bound the N-terminal methionine residue. Similar pegfilgrastim increases proliferation and differentiation neutrophils from committed progenitor cells, induces maturation, enhances survival function mature neutrophils, resulting in dose-dependent neutrophils. After subcutaneous administration, exhibits nonlinear pharmacokinetics exposure more than dose-proportional manner, suggesting that clearance decreases with increased dosing. Filgrastim primarily eliminated by kidney neutrophils/neutrophil precursors; latter presumably involves binding growth G-CSF receptor on cell surface, internalization factor-receptor complexes via endocytosis, subsequent degradation inside cells. Pegylation filgrastim renders renal insignificant, was demonstrated bilaterally nephrectomized rats confirmed subjects impairment. As result, neutrophil-mediated predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, significantly reduced concentration sustained until onset neutrophil recovery. concentrations are longer patients profound neutropenia. Evidence supports use postnadir absolute count (ANC) ≥1 × 109/L as surrogate marker threshold subtherapeutic levels. repeated administration pegfilgrastim, peak decrease, likely due precursor mass. A pharmacokinetic-pharmacodynamic model developed describe pharmacokinetic ANC profiles pegfilgrastim; analysis supported 100 µg/kg an adequate weight-based dose predicted 6 mg would be optimal fixed simplify treatment. Data pivotal study once-per-chemotherapy-cycle injection at safe effective 11 daily injections 5 reducing neutropenia its complications breast cancer receiving four cycles doxorubicin/docetaxel chemotherapy. Because highly efficient regulation precursors, single can given once per chemotherapy cycle conjunction variety myelosuppressive regimens.