title: Pegfilgrastim administered in an abbreviated schedule, significantly improved neutrophil recovery after high-dose radiation-induced myelosuppression in rhesus macaques.
abstract: Conventional daily administration of filgrastim is effective in reducing the duration of severe neutropenia and enhancing survival following lethal radiation, myelosuppressive cytotoxic therapy or myeloablation and stem cell transplantation. A sustained-duration form of filgrastim, pegfilgrastim has significantly simplified scheduling protocols after chemotherapy-induced neutropenia to a single injection while maintaining the therapeutic effectiveness of daily administration of filgrastim. We examined the ability of a single or double (weekly) administration of pegfilgrastim to significantly improve neutrophil recovery in a rhesus macaque model of severe radiation-induced myelosuppression. Animals were exposed to potentially lethal 6 Gy total-body X radiation. After irradiation all animals received supportive care and were administered either pegfilgrastim at 300 μg/kg on day 1 or day 1 and day 7 post exposure, or filgrastim at 10 μg/kg/day initiated on day 1 post exposure and continued daily through neutrophil recovery. Pharmacokinetic parameters and neutrophil-related values for duration of neutropenia, neutrophil nadir, time to recovery to an absolute neutrophil count ≥500/μL or ≥2000/μL, and days of antibiotic support were determined. Effective plasma concentrations of pegfilgrastim were maintained in neutropenic animals until after the onset of hematopoietic recovery, which is consistent with neutrophil-dependent properties of elimination. Administration of pegfilgrastim at day 1 and day 7 was most effective at improving neutrophil recovery compared to daily administration of filgrastim or a single injection of pegfilgrastim on day 1, after severe, radiation-induced myelosuppression in rhesus macaques.
authors.affiliation: Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA. afarese@som.umaryland.edu
authors.forename: A M
authors.initials: AM
authors.lastname: Farese
authors.forename: M V
authors.initials: MV
authors.lastname: Cohen
authors.forename: R B
authors.initials: RB
authors.lastname: Stead
authors.forename: W
authors.initials: W
authors.lastname: Jackson
authors.forename: T J
authors.initials: TJ
authors.lastname: Macvittie
mesh_terms: D000818:Animals; D004334:Drug Administration Schedule; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics / Q000494:pharmacology; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects / Q000528:radiation effects; D011092:Polyethylene Glycols; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D014965:X-Rays
chemical_list: D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim