Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738
Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738
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DOI：
10.1038/srep13545
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发表时间：
2015-08-27
影响因子：
4.6
通讯作者：
Bendtsen, Claus
中科院分区：
文献类型：
--
作者：
Checkley, Stephen;MacCallum, Linda;Bendtsen, Claus
了解药物剂量和计划的治疗效果对临床试验的设计和实施至关重要。单药治疗，特别是联合治疗的复杂性日益增加，对肿瘤药物开发的临床阶段提出了重大挑战。利用系统药理学方法，我们用细胞周期的机制模型扩展了现有的肿瘤生长的pkpd模型，从而模拟了ATR抑制剂AZD6738和电离辐射的单一和联合治疗。使用AZD6738，我们开发了基于多参数细胞的检测方法，测量DNA损伤和细胞周期转变，提供适合模型校准的定量数据。我们的体外校准细胞周期模型可以预测体内小鼠异种移植研究中观察到的肿瘤生长。该模型正用于AZD6738的I期临床试验设计，旨在通过定量剂量和计划预测改善患者护理。
Understanding the therapeutic effect of drug dose and scheduling is critical to inform the design and implementation of clinical trials. The increasing complexity of both mono, and particularly combination therapies presents a substantial challenge in the clinical stages of drug development for oncology. Using a systems pharmacology approach, we have extended an existing PK-PD model of tumor growth with a mechanistic model of the cell cycle, enabling simulation of mono and combination treatment with the ATR inhibitor AZD6738 and ionizing radiation. Using AZD6738, we have developed multi-parametric cell based assays measuring DNA damage and cell cycle transition, providing quantitative data suitable for model calibration. Our in vitro calibrated cell cycle model is predictive of tumor growth observed in in vivo mouse xenograft studies. The model is being used for phase I clinical trial designs for AZD6738, with the aim of improving patient care through quantitative dose and scheduling prediction.