title: Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates.
abstract: Leukocyte growth factors (LGF), such as filgrastim, pegfilgrastim and sargramostim, have been used to mitigate the hematologic symptoms of acute radiation syndrome (ARS) after radiation accidents. Although these pharmaceuticals are currently approved for treatment of chemotherapy-induced myelosuppression, such approval has not been granted for myelosuppression resulting from acute radiation exposure. Regulatory approval of drugs used to treat radiological or nuclear exposure injuries requires their development and testing in accordance with the Animal Efficacy Rule, set forth by the U.S. Food and Drug Administration. To date, filgrastim is the only LGF that has undergone efficacy assessment conducted under the Animal Efficacy Rule. To confirm the efficacy of another LGF with a shorter dosing regimen compared to filgrastim, we evaluated the use of pegfilgrastim (Neulasta(®)) in a lethal nonhuman primate (NHP) model of hematopoietic acute radiation syndrome (H-ARS). Rhesus macaques were exposed to 7.50 Gy total-body irradiation (the LD(50/60)), delivered at 0.80 Gy/min using linear accelerator 6 MV photons. Pegfilgrastim (300 μg/kg, n = 23) or 5% dextrose in water (n = 23) was administered on day 1 and 8 postirradiation and all animals received medical management. Hematologic and physiologic parameters were evaluated for 60 days postirradiation. The primary, clinically relevant end point was survival to day 60; secondary end points included hematologic-related parameters. Pegfilgrastim significantly (P = 0.0014) increased 60 day survival to 91.3% (21/23) from 47.8% (11/23) in the control. Relative to the controls, pegfilgrastim also significantly: 1. decreased the median duration of neutropenia and thrombocytopenia; 2. improved the median time to recovery of absolute neutrophil count (ANC) ≥500/μL, ANC ≥1,000/μL and platelet (PLT) count ≥20,000/μL; 3. increased the mean ANC at nadir; and 4. decreased the incidence of Gram-negative bacteremia. These data demonstrate that pegfilgrastim is an additional medical countermeasure capable of increasing survival and neutrophil-related parameters when administered in an abbreviated schedule to a NHP model of lethal H-ARS.
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Kim G
authors.initials: KG
authors.lastname: Hankey
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.affiliation: b  ACell, Inc., Columbia, Maryland; and.
authors.forename: Erica C
authors.initials: EC
authors.lastname: Blaauw
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Allison M
authors.initials: AM
authors.lastname: Gibbs
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Cassandra P
authors.initials: CP
authors.lastname: Smith
authors.affiliation: c  Department of Biostatistics, Indiana University, School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.affiliation: c  Department of Biostatistics, Indiana University, School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tong
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Karl L
authors.initials: KL
authors.lastname: Prado
authors.affiliation: a  Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D016470:Bacteremia / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D003681:Dehydration / Q000209:etiology / Q000517:prevention & control; D003967:Diarrhea / Q000209:etiology / Q000517:prevention & control; D000069585:Filgrastim; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D011092:Polyethylene Glycols; D011187:Posture; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim