Working with Doses in SimBiology | SimBiology Tutorials for QSP, PBPK, and PK/PD Modeling and Analysis
From the series: SimBiology Tutorials for QSP, PBPK, and PK/PD Modeling and Analysis
Create and apply dose schedules to a model in SimBiology®.
Published: 18 Nov 2014
This video tutorial demonstrates how to apply dosing schedules to a model in SimBiology. In this video, we will use a previously built target-mediated drug disposition model. In this model, receptor reversibly binds with drug to form a receptor drug complex in plasma. Additionally, clearance of the complex and the drug and synthesis and degradation of the receptor are also described via respective reactions.
Using this model, we will show you how different dosing types and dosage regimens can be applied to models using doses feature in SimBiology. In the current version of SimBiology, doses can be modified in the Table overview or Doses view. We will choose to use Doses view. And this will open Doses tab next to Model Diagram tab.
In this previously built model, we have a dosage regimen for a single dose of 4 milligrams. This dose is applied to plasma directly, defined by the target species, Plasma Drug, which displays the characteristics of an intravenous bolus dosing. Doses are applied to the model during simulation. And this can be configured on Task Editor.
To simulate the current model, we will add a simulation task. This opens up the Task Editor. Here, under Doses to Apply panel, let us add the new dosage regimen to the task.
Now we will run the task to visualize the time concentration profiles of the model quantities that is drug receptor, and complex. The Doses feature in SimBiology allows users to create multiple dosing schedules. And they test their effect on model behavior. This lets you test different dosing options without altering the properties of the base model. Let us create a new dosage regimen.
When adding a dose, we have two options to choose from-- a repeat dose or a scheduled dose. A repeat dose lets you configure a repeated dose schedule, where same dose amount is given unequal time intervals. Whereas a schedule dose lets you apply different dose amounts with each dose and lets you apply these doses at desired time intervals. Let us choose the Repeat Dose option and test the repeated dosage regimen, where the subject will be given 4 milligrams of drug daily instead of a single dose.
We will name the dosage regimen 4 milligrams daily. Once a dose name and type are specified and added, you can further configure the dosage regimen using the Settings panel. Right next to the Settings panel, there's a description panel that lets you add notes for each dosage regimen. The first property that needs to be defined on Settings panel is the target name. When a dose is applied via doses during a simulation, the value of the dose component is appropriately varied during the simulation, according to the specified dosing parameters.
The species that the doses applied to is specified by target name. We will define plasma drug as the dose species. Duration parameter name and lag parameter name are optional properties. And duration parameter name represents the duration of drug absorption when absorption follows zero order kinetics. And lag parameter name represents the time lag for any dose type. We will leave these blank.
The time of the first dose is defined by start time property. We will leave it at default value 0. And among property is the amount of dose given with each dose. Since we will be applying 4 milligrams dose each time, we will set amount to 4 and amount units to milligrams.
Default value 0 on rate property indicates the doses given instantaneously. If you would like to define how fast each dose is given, you can define the rate property. The time interval between each dose is defined by interval property. We would like to give the dose daily. Therefore, we will set this to 1 and time units to day. Units on time will apply to both interval and start time properties.
Finally, repeats count indicates the number of doses that will be given in total. We will set this to 5. Note that the repeat count corresponds to the number of additional doses. For example, if repeat count is set to 4, this corresponds to five total doses, one at start time and four more every interval time, as shown on the dosing plot on the bottom right corner.
Let us add the new dosage regimen to the task. Note that one or more dosing schedules can be applied to model simultaneously. The checkbox here indicates that the dose will be applied to the model during simulation. We will uncheck the previous dose so that we test only the most recent dose.
Keep in mind that doses are added to the base model values in SimBiology. Therefore, unless you want the dose to be added on top of the value in base model, set the base value on target species to 0. We will change stop time on the task to six days so it's in the same scale with our dosage regimen. And we will run the task to visualize the time concentration profile of model quantities.
Now, we can see that drug concentration reaches almost 0 every day, and increases back to the desired concentration approximately 20 milligrams per liter with every dose. If you would like to be more flexible on your dosing schedule, for example, dosing drug at different time intervals, then you can use a scheduled dose. We will create a new dose schedule called non-periodic.
Each dose in a scheduled dose can have a different amount, as defined by an amount array in the amount property. And similarly, each dose can be given at specified times, as defined by a time array in the time property. In order to configure this, you can either use a schedule table or Editor. We will use Editor.
We will define a non-periodic dose schedule, using a custom function, non-periodic. First input in this function, define the days of the week the dose will be given. And last input defines the duration of the dosage regimen in weeks. We will be dosing on Monday, Wednesday, and Friday for three weeks.
Similarly, we will define the dose amount array in order to dose 4mg with every dose. We will create an array using ones function, which creates an array of whole ones. We will define the size of this array to be the same size as the time array, and multiply it with 4 so that we have an array of all 4's. Finally, we will configure units.
At each time point in the time array, a dose will be given with the corresponding amount. We will add the new dose schedule to the current task and uncheck the previous dose schedule so that we test only the most recent dose. Before running the task, let us change the stop time to 20 days in order to be in the same scale with the dose schedule. We will run the task with the scheduled dose to visualize the updated time concentration profile of model quantities.
So far, we showed you how to create multiple dose schedules and test their effect on model behavior Furthermore, you can use doses to interactively explore how different dosing strategies change time concentration profiles of model quantities. This can be done using Explorer tools.
On the Explorer tools panel, under Adjust Dose option, we have the option to explore either an already existing dosing schedule or create a dose schedule from scratch. We will choose 4 milligram daily dose schedule that we have created. Notice that the dose schedule is applied to the Explorer panel. This lets you explore model dynamics. That is how drug complex and receptor concentration change over time as a function of dose amount, rate, and dose time interval. We will uncheck the previous dose and explore model dynamics using sliders in order to find the desired dosage regimen.
If you choose to overlay a results option, you can see the concentration variation plotted on the same plot. This concludes this video. You can now try using a dose schedule on your own model or watch another video.