Crossover design supports two data formats: data for both treatments stacked in one column, or each treatment placed in a separate column. An example of each follows.
Data stacked in one column
For this type of data, all the data for one treatment must be displayed in the first rows, followed by all the data for the other treatment.
1. Select File > Import or click the Import button. The Open File(s) dialog is displayed.
2. Navigate to the Phoenix examples directory, which by default is located at C:\Program
Files\Pharsight\Phoenix\applica-tion\Examples.
3. Select stacked.CSV and click Open.
The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented.
4. Click Finish. The data set is added to the project’s Data folder.
A data set in CSV (Comma Separated Value) format is added to the Data folder as a worksheet.
5. View the data set by selecting it in the Data folder. Select the worksheet to display it in the Grid tab.
Insert a Crossover object:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Crossover.
The Crossover object is added to the workflow in the Object Browser.
2. Map the data set stacked as the input source for the Crossover object:
• Use the pointer to drag the stacked worksheet from the Data folder to the Crossover object’s Main Mappings panel.
OR
• In the Crossover Main Mappings panel click the Select source button to open the Select Object dialog.
• Select the stacked worksheet and click Select.
The stacked data set is mapped to the Crossover object.
3. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:
• Map TREATMENT to the Treatment context.
• Map SUBJECT to the Subject context.
• Map PARAMETER to the Sort context.
• Map ESTIMATE to the Response context.
• Leave PERIOD mapped to None.
• Map SEQUENCE to the Sequence context.
The Crossover object computes confidence intervals for treatment medians and median difference between treatments, the results of which are displayed in the Confidence Intervals worksheet.
The Crossover object also estimates the relevance of direct, residual, and period effects as well as treatment and residual effects. These results are displayed in the Effects worksheet.
Data in separate columns
1. Select File > Import or click the Import button. The Open File(s) dialog is displayed.
2. Navigate to the Phoenix examples directory, which by default is located at C:\Program
Files\Pharsight\Phoenix\applica-tion\Examples.
3. Select separate.CSV and click Open.
4. Click Finish. The data set is added to the project’s Data folder.
Insert a Crossover object:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Crossover.
The Crossover object is added to the workflow in the Object Browser.
Note: When multiple objects of the same type are added to a workflow they are numbered sequentially. For example, the second Crossover object added to this workflow is called Crossover 1.
2. Map the data set separate as the input source for the Crossover 1 object:
• Use the pointer to drag the separate worksheet from the Data folder to the Main Mappings panel.
OR
• In the Crossover 1 Main Mappings panel click the Select source but-ton to open the Select Object dialog.
• Select the separate worksheet and click Select.
The separate data set is mapped to the Crossover 1 object.
The treatment data layout must be specified before the data can be mapped to the contexts for the Crossover 1 object.
Use the Options tab to specify settings for the Crossover model options. The Options tab is located underneath the Setup tab.
3. Select Separate in the Treatment Data Layout menu.
4. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:
• Map Sequence to the Sequence context.
• Map Subject to the Subject context.
• Map trt_G to the Test Treatment context.
• Map trt_H to the Reference Treatment context.
5. Click the Execute button. The results are displayed on the Results tab.
The Confidence Intervals worksheet contains treatment medians, median differ-ences between treatments, and confidence intervals for those estimates.
The Effects worksheet provides statistics for direct, residual, and period effects, as well as the effect of treatment and residual simultaneously.
Deconvolution
Perhaps the most common application of deconvolution is in the evaluation of drug release and drug absorption from orally administered drug formulations. In this case, the bioavailability is evaluated if the reference input is a vascular drug input. Similarly, gastro-intestinal release is evaluated if the reference is an oral solution (oral bolus input). Both are included here.
This example uses the data set M3tablet.dat, which is located in the Phoenix examples directory, which is located by default at C:\Program
Files\Pharsight\Phoenix\application\Examples. The analysis objectives are to estimate the following for a tablet formulation:
1. Absolute bioavailability and rate and cumulative extent of absorption over time.
2. In vivo dissolution and the rate and cumulative extent of release over time.
Absolute bioavailability: To estimate the absolute bioavailability, the mean unit impulse response parameters A and alpha have already been estimated from concentration-time data following instantaneous input (IV bolus) for three sub-jects, using PK model 1. The data in M3tablet.dat includes those parameter esti-mates and plasma drug concentrations following oral administration of a tablet formulation. This example shows how to estimate the rate at which the drug reaches the systemic circulation, using deconvolution.
Dissolution: To estimate the in vivo dissolution from the tablet formulation, the mean unit impulse response parameters A and alpha have already been esti-mated from concentration-time data following instantaneous input into the gastro-intestinal tract by administration of a solution, using PK model 3. The steps below show how to use deconvolution to estimate the rate at which the drug dissolves.
Absolute bioavailability
Evaluate absolute bioavailability:
For this type of data, all the data for one treatment must be displayed in the first rows, followed by all the data for the other treatment.
1. Select File > Import or click the Import button. The Open File(s) dialog is displayed.
2. Navigate to the Phoenix examples directory, which by default is located at C:\Program
Files\Pharsight\Phoenix\applica-tion\Examples.
3. Select M3tablet.dat and click Open.
The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented.
4. Click Finish. The data set is added to the project’s Data folder.
5. View the data set by selecting it in the Data folder.
Start the evaluation:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Deconvolution.
The Deconvolution object is added to the workflow in the Object Browser.
2. Map the data set M3tablet as the input source for the Deconvolution object:
• Use the pointer to drag the M3tablet worksheet from the Data folder to the Deconvolution object’s Main Mappings panel.
OR
• In the Deconvolution Main Mappings panel click the Select source but-ton to open the Select Object dialog.
• Select M3tablet and click Select.
The M3tablet data set is mapped to the Deconvolution object.
3. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:
• Map subject to the Sort context.
• Map time to the Time context.
4. Select Exp Terms in the Setup list.
5. Select the Use internal Worksheet check box.
6. In the Value column type 100 for each A1 cell in the Parameter column.
7. In the Value column type 0.98 for each Alpha1 cell in the Parameter column.
Note: Type 100 and 0.98 in the first two cells underneath Value. Highlight the cells and drag the selection down to fill the Value column.
There are no dose amounts for this example. The calculated fractional input approaches a value of 1 rather than being adjusted for dose amount.
8. Click the Execute button. The results are displayed on the Results tab.
Phoenix generates worksheets and plots for the output. Partial results for subject 1 are displayed below.
Worksheet output Values worksheet
Plot output
Cumulative Rates plot
Dissolution
For the rest of this example an oral solution (a.k.a. oral bolus) is used to estimate the unit impulse response. In this case, the deconvolution result should be inter-preted as an in vivo dissolution profile, not as an absorption profile. The oral impulse response function should have the property of the initial value being equal to 0, which implies that the sum of the A’s must be zero. The alphas should all still be positive, but at least one of the A’s will be negative.
Evaluate dissolution:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Deconvolution.
The Deconvolution object is added to the workflow in the Object Browser.
Note: When multiple objects of the same type are added to a project they are num-bered sequentially. For example, the second Deconvolution object added to this project is called Deconvolution 1.
2. Map the data set M3tablet as the input source for the Deconvolution 1 object:
• Use the pointer to drag the M3tablet worksheet from the Data folder to the Deconvolution 1 object’s Main Mappings panel.
• In the Deconvolution 1 Main Mappings panel click the Select source button to open the Select Object dialog.
• Select M3tablet and click Select.
The M3tablet data set is mapped to the Deconvolution 1 object.
3. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:
• Map subject to the Sort context.
• Map time to the Time context.
• Map conc to the Concentration context.
• Leave all the other data types mapped to None.
Use the Options tab to specify settings for the Deconvolution model options. The Options tab is located underneath the Setup tab.
4. Select 2 in the Exponential Terms menu.
5. Select Exp Terms in the Setup list.
6. Select the Use internal Worksheet check box.
7. In the Value column type -110 for each A1 cell in the Parameter column.
8. In the Value column type 3.8 for each Alpha1 cell in the Parameter column.
9. In the Value column type 110 for each A2 cell in the Parameter column.
10.In the Value column type 0.10 for each Alpha2 cell in the Parameter column.
Note: After the values have been entered for subject 1, highlight all four cells for subject 1 and drag the selection down to copy the A and Alpha values to sub-jects 2 and 3.
11.Click the Execute button. The results are displayed on the Results tab.
Phoenix generates the new worksheet and graphs. Results for subject 1 are dis-played below:
Worksheet output Values worksheet
Plot output
Cumulative Rates plot
Note: It is not necessary to keep a project open after completing each chapter. This project is not required when working in the next chapter. To close a project right-click the project and select Close Project.