title: The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent.
abstract: The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 h following total body irradiation in a non-human primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gy, (target lethal dose 50/60) delivered at 0.80 Gy min, using linear accelerator-derived 6 MV photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg d) or the control (5% dextrose in water) was administered subcutaneously daily through effect (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 h post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 h after irradiation, did not improve survival (2.5% increase, p = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure.
authors.affiliation: *Radiation Oncology Department, University of Maryland, School of Medicine, Baltimore, MD; †Department of Biostatistics, Indiana University, Indianapolis, IN.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Brown
authors.forename: Cassandra P
authors.initials: CP
authors.lastname: Smith
authors.forename: Allison M
authors.initials: AM
authors.lastname: Gibbs
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Johnson
authors.forename: Karl L
authors.initials: KL
authors.lastname: Prado
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000528:radiation effects; D004912:Erythrocytes / Q000187:drug effects / Q000528:radiation effects; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000528:radiation effects; D011994:Recombinant Proteins / Q000494:pharmacology; D015996:Survival Rate; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim