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Scan Dosing Regimens Using SimBiology Model Analyzer App

This example shows how to assess the efficacy and toxicity of various dose amounts in theSimbiology模型Analyzer通过使用目标（受体）占用率作为生物标志物。该示例使用目标介导的药物处置（TMDD）模型[1]with slight modifications.

Target-Mediated药物处置(TMDD)模型

靶介导的药物处置（TMDD）是一种现象，其中药物与其药理靶位部位具有高亲和力（例如受体或酶），在这种相互作用中反映在药物的药物特征中。

This example uses a modified TMDD model based on the model used by Mager and Jusko[1]with a minor adjustment. The authors proposed a generic TMDD model that accounted for saturable drug-target binding and target (or receptor) mediated elimination.药品在里面等离子体可逆地与未结合的目标to form the drug-target复杂的。Kon和科夫分别是关联和解离速率常数。自由清除药品和复杂的来自等离子体is described by first-order processes with rate constants —kel和公里， 分别。零级合成率描述了自由目标周转率ksyn和a first-order elimination (the rate constant,KDEG). Variants of the TMDD model have been since used to characterize the pharmacokinetics of numerous drugs.

Mager和Jusko提出的模型的调整如下。

  • 目标占用（TO) is modeled asTO=复杂的/（（目标+复杂的)， 在哪里TO是一个参数，复杂的和目标are species.

使用不同剂量探索模型响应

Investigate the model response on the target occupancy (TO）使用不同的剂量量。

Load TMDD Model

在Matlab®命令行，输入：

simBiologyModelAnalyzer("tmdd_with_TO.sbproj")

生成一系列剂量和模拟模型

首先，创建一个程序以生成不同剂量量的剂量数量，范围从0到300纳米尔。

  1. 选择Program>Generate Samples。

  2. 在里面Generate Samples步骤，双击空单元Component Name并输入Daily Dose.Amount。

  3. UnderDaily Dose.Amount, set类型toMATLAB代码, and setCodetolinspace（0,300,31）。This code specifies the generation of 31 doses with amounts ranging from 0 to 300 nanomoles.

  4. Disable the plotting of dose samples by clicking the plot button, as shown in the figure.

  5. Add a simulation step to simulate the model using the defined doses. Click the (+) icon at the upper left of the program and select模拟。A模拟step appears following theGenerate Samplesstep.

  6. 在里面模型步骤，单击登录的状态。选择TO作为唯一通过清除所有其他复选框来登录的状态。

  7. On theHometab, clickRun。

    Once the simulation is complete, the program plots the results inplot1，其中显示了模型响应的时间过程（TO) given different dose amounts.

    Tip

    Plots are backed by data that are currently present in the app workspace. Plots are not snapshots. When the data (either experimental data or simulation results) is removed or changed, the plots are also updated according to the changes in the underlying data.

定义最大和最小目标入住阈值

调查哪些剂量量对应于TOresponses that lie within the safety (至= 0.85) and efficacy (TO = 0.15) thresholds. One approach is to add two (horizontal) threshold lines to theTOresponse plot.

  1. On theHome标签，在Projectsection, clickNew Datasheet。

  2. 在里面浏览器窗格，扩展Program1文件夹，然后扩展Lastrunfolder.

  3. 拖results进入新的数据表。数据表现在显示time和TO具有相应值的列。

  4. Point to the table and add an expression by clicking the (+) icon that appears at the top right.

    Note

    每当您将表达式添加到包含来自Lastrun, the expression is added as an可观察对象到模型。除此之外后处理：计算可观察结果步骤还添加到生成的相应程序中Lastrundata.

  5. Double-clickName1并重命名EfficacyThreshold。

  6. Double-click单位并输入dimensionless。

  7. Double-click the表达cell and enter0.15。该表达式在每个时间点都以相同的常数值（0.15）填充列。

  8. 同样，添加另一个表达式列安全嫌疑人with the expression0.85。扩张results在里面Lastrunfolder. The values from these two expression columns are scalar-valued可观察s现在存放在名称的表中标量underresults。

    现在，您可以将最大和最小阈值线绘制到现有图plot1。

  9. 点击plot1标签。按Ctrl和selectEfficacyThreshold和安全嫌疑人variables from the浏览器pane. Drag them into the plot. The plot now showsTOprofiles along with the efficacy and safety threshold lines.

可视化目标占用率响应在单独的轴上

The plot shows that certainTOresponses either exceed the safety threshold or dip below the efficacy threshold. To better visualize this observation, you can customize the plot to see each dose amount and the correspondingTOresponse on separate axes.

  1. 在里面属性编辑器， 在里面Visual Channelstable, setResponsestoColor和Scenariosto网格。

  2. ClickPlot Settings。为了绘制Ylabel, enterTO作为值。

  3. 在里面轴限制section, selectLink Y-Axis在y-axis for all subplots.

Postprocess Simulation Results

In addition to visually inspecting each response plot on separate axes, you can add a postprocessing step to query exactly which dose amounts stay within the thresholds.

  1. 点击Program1标签。在里面后处理：计算可观察结果步骤，双击第一个空单元Name列输入：feasible_doses。

  2. 在里面表达列，输入最大（TO）<0.85＆min（to）> 0.15。将单元设置为dimensionless。

    Note

    Anytime you add an expression to the可观察到步骤中的表，将自动添加表达式可观察对应模型的对象。

  3. 选择feasible_doses作为唯一可观察的。清除EfficacyThreshold和安全嫌疑人。

  4. 评估feasible_doses, run just the simulation step by clicking the run button at the top of the模拟step.

运行程序步骤生成以下图。您可能会看到有关尺寸分析无法执行的警告。出于本示例的目的，您可以忽略警告。

Display both the x-grid and y-grid by clicking两个都在里面网格section. Thex- 轴代表剂量量和y- 轴代表剂量数量是否生成TO保留在安全性和有效性阈值（值为1）（值为0）内的响应。

The plot shows that dose amounts ranging from50to180纳莫尔斯提供TO所需的功效和安全阈值范围内的响应。

See Also

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相关话题

参考

[1]Marger, D., and W. Jusko. 2001. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition.药代动力学和药效学杂志。28：507–532。