Department of Biomedical Engineering, University of Southern California, Los Angeles, California, 90089, USA.
Pfizer Worldwide Research, Development and Medicine, San Diego, California, USA.
AAPS J. 2020 Nov 6;22(6):143. doi: 10.1208/s12248-020-00529-x.
The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug's mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model's drug effect parameters. Population simulations were performed to predict the absolute neutrophil count (ANC) and incidence of neutropenia for each compound, which were compared to results reported in the literature. In addition, using the single agent in vitro study results, the model was able to predict ANC time course in response to paclitaxel plus carboplatin in combination, which compared favorably to the results reported in a phase 1 clinical trial of 46 patients (r = 0.70). Model simulations were used to compare the relative risk (RR) of neutropenia in patients with high baseline ANCs for five chemotherapeutic regimens: doxorubicin (RR = 0.59), paclitaxel plus carboplatin combination (RR = 0.079), carboplatin (RR = 0.047), paclitaxel (RR = 0.031), and gemcitabine (RR = 0.013). Finally, the model was applied to quantify the reduced incidence of neutropenia with coadministration of pegfilgrastim or filgrastim, for both paclitaxel and the combination of paclitaxel plus carboplatin. The model provides a framework for predicting clinical neutropenia using in vitro bone marrow studies of anticancer agents that may guide drug development decisions.
在药物早期开发中预测化疗引起的中性粒细胞减少症的发生率，可以为风险监测和缓解策略提供信息，并为将化合物推进临床试验的决策提供依据。在本报告中，我们扩展了一种包含药物对骨髓祖细胞细胞周期增殖作用机制的粒细胞生成生理模型，以纳入细胞毒性药物紫杉醇、卡铂、多柔比星和吉西他滨的作用。对每种化合物进行了体外骨髓研究，并使用研究结果确定了模型的药物效应参数。进行了群体模拟以预测每种化合物的绝对中性粒细胞计数（ANC）和中性粒细胞减少症的发生率，并将预测结果与文献中报告的结果进行了比较。此外，使用单一药物的体外研究结果，模型能够预测紫杉醇加卡铂联合用药时 ANC 的时间过程，与 46 例患者的 1 期临床试验报告的结果（r = 0.70）相比，该模型具有可比性。模型模拟用于比较基线 ANC 较高的患者五种化疗方案发生中性粒细胞减少症的相对风险（RR）：多柔比星（RR = 0.59）、紫杉醇加卡铂联合用药（RR = 0.079）、卡铂（RR = 0.047）、紫杉醇（RR = 0.031）和吉西他滨（RR = 0.013）。最后，该模型用于量化培非格司亭或非格司亭与紫杉醇和紫杉醇加卡铂联合用药时中性粒细胞减少症发生率降低的情况。该模型为使用抗癌药物的体外骨髓研究预测临床中性粒细胞减少症提供了一个框架，可为药物开发决策提供指导。
