Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates

Kim G. Hankey, Ann M. Farese, Erica C. Blaauw, Allison M. Gibbs, Cassandra P. Smith, Barry Katz, Yan Tong, Karl L. Prado, Thomas J. MacVittie

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 LD50/60), 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.

Original languageEnglish (US)
Pages (from-to)643-655
Number of pages13
JournalRadiation Research
Volume183
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

neutrophils
primates
leukocytes
Primates
Acute Radiation Syndrome
animals
radiation
Neutrophils
Intercellular Signaling Peptides and Proteins
Leukocytes
countermeasures
radiation dosage
linear accelerators
chemotherapy
schedules
accidents
platelets
Radioactive Hazard Release
drugs
incidence

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Hankey, K. G., Farese, A. M., Blaauw, E. C., Gibbs, A. M., Smith, C. P., Katz, B., ... MacVittie, T. J. (2015). Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. Radiation Research, 183(6), 643-655. https://doi.org/10.1667/RR13940.1

Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. / Hankey, Kim G.; Farese, Ann M.; Blaauw, Erica C.; Gibbs, Allison M.; Smith, Cassandra P.; Katz, Barry; Tong, Yan; Prado, Karl L.; MacVittie, Thomas J.

In: Radiation Research, Vol. 183, No. 6, 01.06.2015, p. 643-655.

Research output: Contribution to journalArticle

Hankey, KG, Farese, AM, Blaauw, EC, Gibbs, AM, Smith, CP, Katz, B, Tong, Y, Prado, KL & MacVittie, TJ 2015, 'Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates', Radiation Research, vol. 183, no. 6, pp. 643-655. https://doi.org/10.1667/RR13940.1
Hankey KG, Farese AM, Blaauw EC, Gibbs AM, Smith CP, Katz B et al. Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. Radiation Research. 2015 Jun 1;183(6):643-655. https://doi.org/10.1667/RR13940.1
Hankey, Kim G. ; Farese, Ann M. ; Blaauw, Erica C. ; Gibbs, Allison M. ; Smith, Cassandra P. ; Katz, Barry ; Tong, Yan ; Prado, Karl L. ; MacVittie, Thomas J. / Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. In: Radiation Research. 2015 ; Vol. 183, No. 6. pp. 643-655.
@article{ee2005a00b7040c99520a6bdf107289f,
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{\circledR}) 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 LD50/60), 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.",
author = "Hankey, {Kim G.} and Farese, {Ann M.} and Blaauw, {Erica C.} and Gibbs, {Allison M.} and Smith, {Cassandra P.} and Barry Katz and Yan Tong and Prado, {Karl L.} and MacVittie, {Thomas J.}",
year = "2015",
month = "6",
day = "1",
doi = "10.1667/RR13940.1",
language = "English (US)",
volume = "183",
pages = "643--655",
journal = "Radiation Research",
issn = "0033-7587",
publisher = "Radiation Research Society",
number = "6",

}

TY - JOUR

T1 - Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates

AU - Hankey, Kim G.

AU - Farese, Ann M.

AU - Blaauw, Erica C.

AU - Gibbs, Allison M.

AU - Smith, Cassandra P.

AU - Katz, Barry

AU - Tong, Yan

AU - Prado, Karl L.

AU - MacVittie, Thomas J.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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 LD50/60), 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.

AB - 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 LD50/60), 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.

UR - http://www.scopus.com/inward/record.url?scp=84931426440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931426440&partnerID=8YFLogxK

U2 - 10.1667/RR13940.1

DO - 10.1667/RR13940.1

M3 - Article

VL - 183

SP - 643

EP - 655

JO - Radiation Research

JF - Radiation Research

SN - 0033-7587

IS - 6

ER -