用 G-CSF 治疗的非人类灵长类动物中性粒细胞减少症的辐射损伤定量及其与绝对中性粒细胞计数时间过程和总生存时间之间的关系。
Quantification of Radiation Injury on Neutropenia and the Link between Absolute Neutrophil Count Time Course and Overall Survival in Nonhuman Primates Treated with G-CSF.
机构信息
Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., Thousand Oaks, California, USA.
Seattle Genetics, Bothell Washington, Massachusetts, USA.
出版信息
Pharm Res. 2020 May 21;37(6):102. doi: 10.1007/s11095-020-02839-3.
PURPOSE
To 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.
METHODS
Source 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.
RESULTS
The 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.
CONCLUSION
The 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.
目的
建立中性粒细胞绝对计数（ANC）对急性辐射（AR）暴露反应的模型，并评估 ANC 时间过程作为 AR 暴露后总生存（OS）的预测因子，包括 AR 暴露后有无粒细胞集落刺激因子（G-CSF）治疗。
方法
来源于在恒河猴中进行的两项关键研究的数据，这些猴子在第 0 天接受 750cGy 全身照射，分别接受安慰剂、每日非格司亭或培非格司亭（照射后第 1 天和第 8 天）。动物观察 60 天，每隔 1-2 天测量 ANC。 ANC 对 AR 反应的群体模型和观察到的 ANC 时间过程与 OS 之间的联系由三个子模型组成，这些子模型描述了辐射损伤、粒细胞生成和 OS 的时间事件模型。
结果
ANC 反应模型准确描述了 AR 暴露对中性粒细胞减少持续时间的影响。ANC 是生存的有效替代指标，因为它分别解释了非格司亭和培非格司亭治疗效果的 76%（95%CI，41%-97%）和 73.2%（95%CI，38.7%-99.9%）。
结论
将目前将辐射损伤与中性粒细胞减少和 ANC 时间过程与 OS 联系起来的模型，可以作为将这些影响转化为人类的基础。
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