BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems
BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems
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DOI：
10.1007/s10928-011-9229-x
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发表时间：
2012-02-01
影响因子：
2.5
通讯作者：
Zavodszky, Maria I.
中科院分区：
文献类型：
--
作者：
Graf, John F.;Scholz, Bernhard J.;Zavodszky, Maria I.
我们开发了一种详细的全身生理药代动力学（PBPK）建模工具，用于计算药物在人体或动物的各种组织和器官中随时间的分布。常微分方程（ODE）在宏观水平上描述了体液通过器官和组织的循环，在分子水平上描述了细胞及其细胞器内的生物运输机制和生物转化。身体中的每个主要器官被建模为由一个或多个组织组成。组织由细胞和液体空间组成。该模型考虑了动脉和静脉血液以及淋巴的循环。由于需要准确预测显像剂的药代动力学特性，因此BioDMET的发展比大多数PBPK模型更复杂。模型的解剖细节对于成像模拟终点很重要。模型复杂性对于快速调整工具以适应不同的问题而无需为每个问题生成新模型也至关重要。当更简单的模型是首选时，非关键隔室可以动态地折叠，以减少不必要的复杂性。BioDMET已用于肿瘤学、神经病学、心脏病学和糖尿病学中的成像可行性计算。为此，将由模型生成的时间浓度数据输入到基于物理的图像模拟器中以建立成像标准。然后，这些用于定义成功成像所需的药剂和生理特性范围。BioDMET最近已被用于帮助开发抗菌疗法。鉴于一系列内置功能及其固有的自定义灵活性，该模型可用于研究各种药代动力学和药效学问题，如个体间差异和疾病状态对药物药代动力学和药效学的影响，剂量优化和种间缩放。在开发一种工具来帮助成像剂和药物开发的同时，我们的目标是通过提供一种免费的机械PBPK软件来加速PBPK建模的接受和广泛使用，该软件用户友好，即使是非程序员也易于适应各种问题，提供了现成的参数化模型和从同行评审文献中收集的基准数据。
We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter-species scaling. While developing a tool to aid imaging agent and drug development, we aimed at accelerating the acceptance and broad use of PBPK modeling by providing a free mechanistic PBPK software that is user friendly, easy to adapt to a wide range of problems even by non-programmers, provided with ready-to-use parameterized models and benchmarking data collected from the peer-reviewed literature.