Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinetic studies of granulocyte disposition in healthy humans to characterize the dynamics of neutrophil margination in the presence of endogenous granulocyte-colony stimulating factor (G-CSF). In addition, previously published data from healthy volunteers following pegfilgrastim and filgrastim were used to quantify the regulatory effects of support G-CSF therapies on granulopoiesis. The model was evaluated for the cell cycle inhibitor palbociclib, using an in vitro system of human bone marrow mononuclear cells to quantify the action of palbociclib on proliferating progenitor cells, including its inhibitory effect on G1 to S phase transition. The in vitro results were incorporated into the physiological model of granulopoiesis and used to predict the time course of absolute neutrophil count (ANC) and the incidence of neutropenia observed in three previously reported clinical trials of palbociclib. The model was able to predict grade 3 and 4 neutropenia due to palbociclib treatment with 86% accuracy based on in vitro data.

中文翻译：

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粒细胞生成的生理模型可通过体外骨髓研究预测临床药物诱导的中性粒细胞减少：应用于细胞周期抑制剂。

中性粒细胞减少症是与抗癌药物治疗相关的最常见的剂量限制性毒性反应。基于早期药物开发中药物体外研究的预测中性粒细胞减少症可能性和严重性的能力将有助于推动安全有效的化合物进入人体测试。为此，提出了一种粒细胞生成的生理模型及其调节，其中包括骨髓祖细胞周期，从而可以基于体外研究以机械方式表示相关抗癌药物的作用。模型开发使用了先前报道的健康人类中粒细胞处置的示踪动力学研究数据，以表征在存在内源性粒细胞集落刺激因子（G-CSF）时中性粒细胞边缘化的动力学。此外，pegfilgrastim和filgrastim之后来自健康志愿者的先前发表的数据用于量化支持性G-CSF治疗对粒细胞生成的调节作用。使用人骨髓单核细胞体外系统评估该模型的细胞周期抑制剂palbociclib，以量化palbociclib对增殖祖细胞的作用，包括其对G1到S相转变的抑制作用。将体外结果纳入粒细胞生成的生理模型中，并用于预测在先前报道的三项palbociclib临床试验中观察到的绝对中性粒细胞计数（ANC）的时程和中性白细胞减少症的发生率。根据体外数据，该模型能够预测由于palbociclib治疗引起的3级和4级中性粒细胞减少症，准确率达86％。