Abstract
PurposeTo model absolute neutrophil count (ANC) suppression in response to acute radiation (AR) exposure and evaluate ANC time course as a predictor of overall survival (OS) in response to AR exposure with or without treatment with granulocyte colony-stimulating factor in nonhuman primates.MethodsSource data were obtained from two pivotal studies conducted in rhesus macaques exposed to 750 cGy of whole body irradiation on day 0 that received either placebo, daily filgrastim, or pegfilgrastim (days 1 and 8 after irradiation). Animals were observed for 60 days with ANC measured every 1 to 2 days. The population model of ANC response to AR and the link between observed ANC time course and OS consisted of three submodels characterizing injury due to radiation, granulopoiesis, and a time-to-event model of OS.ResultsThe ANC response model accurately described the effects of AR exposure on the duration of neutropenia. ANC was a valid surrogate for survival because it explained 76% (95% CI, 41%–97%) and 73.2% (95% CI, 38.7%–99.9%) of the treatment effect for filgrastim and pegfilgrastim, respectively.ConclusionThe current model linking radiation injury to neutropenia and ANC time course to OS can be used as a basis for translating these effects to humans.
Highlights
Acute radiation syndrome (ARS) is caused by exposure of large parts of the body to lethal amounts of penetrating radiation over 102 Page 2 of 11Pharm Res (2020) 37: 102 a short period
The current model linking radiation injury to neutropenia and absolute neutrophil count (ANC) time course to overall survival (OS) can be used as a basis for translating these effects to humans
Mortality rate was lower in the groups treated with Granulocyte colonystimulating factors (G-CSFs) compared with the respective placebo groups, and mortality rates were similar between the filgrastim and pegfilgrastim treatment arms
Summary
Acute radiation syndrome (ARS) is caused by exposure of large parts of the body to lethal amounts of penetrating radiation over 102 Page 2 of 11Pharm Res (2020) 37: 102 a short period. Granulocyte colonystimulating factors (G-CSFs) such as filgrastim and pegfilgrastim have the potential to treat HS-ARS [2,3]. Pegfilgrastim is a long-acting G-CSF produced by covalently binding a 20-kD polyethylene glycol molecule to the N-terminal methionine residue of filgrastim with a half-life ranging from 15 to 80 h [3]. Both filgrastim and pegfilgrastim have been found to decrease the depth and duration of neutrophil suppression during myelosuppressive chemotherapy and to reduce the incidence of infection characterized by febrile neutropenia [6,7,8,9,10]. Administration of G-CSF therapy (filgrastim or pegfilgrastim) could potentially be useful in promoting recovery of absolute neutrophil count (ANC) as well as reducing the rates of infection and mortality in patients with HS-ARS
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