» Noncompartmental analysis with exclusions, computing partial areas on page 46.
» Additional NCA examples on page 51: NCA for sparse sampling and drug effect data.
A noncompartmental analysis of three profiles
Suppose a researcher has obtained time and concentration data following oral administration of a test compound to three subjects, and wants to perform non-compartmental analysis and summarize the results.
The data
Data for this example are located in the Phoenix examples directory, which by default is located at C:\Program
Files\Pharsight\Phoe-nix\application\Examples.
Create a new project:
1. Select File > New Project to create a new project. A new project is created in the Object Browser.
2. Name the new project NCA.
Import the data set:
1. Select File > Import or click the Import button. The Open File(s) dialog is displayed.
2. Navigate to the Phoenix examples subdirectory, which by default is located at C:\Program
Files\Pharsight\Phoenix\applica-tion\Examples.
3. Select Bguide1.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. The worksheet is dis-played in the Grid tab, which is located in the right viewing panel.
Note: To view a worksheet in its own window, select the worksheet and double-click it or press ENTER. The worksheet is displayed in its own window.
Use the Units Builder to add units to a column:
Units must be added to the time and concentration columns before the data set can be used in a noncompartmental analysis.
1. Select Bguide1 in the Data folder. The worksheet is displayed in the Grid tab in the right viewing panel.
The Columns tab is located underneath the Grid tab. The Columns tab is used to edit columns in a worksheet.
2. Select the Time column header in the Columns box.
3. Click the Unit Builder button. The Units Builder dialog is displayed.
4. Select hour [hr] in the Time menu.
5. Click the Add button beside the Time menu.
After clicking the Add button the selected units are displayed in the New Units field.
Note: Units can also be typed directly into the New Units field.
6. Click OK to assign the units to the column.
7. Select the Conc column header in the Columns box.
8. Click the Unit Builder button.
9. Select nano [n] in the Mass prefix menu.
10.Select gram [g] in the Mass unit menu.
11.Click the Add button beside the Mass menus.
12.Click the / operator button in the Add operator area.
13.Select milli [m] in the Volume prefix menu.
14.Select liter [L] in the Volume unit menu.
15.Click the Add button beside the Volume menus. Click OK.
Note: Units added to ASCII data sets can be preserved if the data sets are saved in .dat or .csv file formats. Phoenix adds the units to a row below the column headers. To import a .dat or .csv file with units, select the Has units row check box in the File Options area in the Worksheet Import Options dialog.
The model
Noncompartmental analysis for extravascular dosing is available as Model 200 in the Phoenix model library. Phoenix displays the model type (Plasma, Urine, or Drug Effect) in the Options tab of an NCA object.
Note: The exact model used is determined by the dose type. Extravascular Input uses Model 200, IV-Bolus Input uses Model 201, and Constant Infusion uses Model 202.
Insert the NCA object:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > NCA.
The NCA object is added to the workflow in the Object Browser.
Objects automatically open in the right viewing panel when they are inserted in a workflow.
Each object’s default view is the Setup tab, which contains all the steps neces-sary to set up an object.
2. Map the data set Bguide1 as the input source for the NCA object:
• Use the pointer to drag the Bguide1 worksheet from the Data folder to the NCA object’s Main Mappings panel.
• In the NCA Main Mappings panel click the Select source button to open the Select Object dialog.
• Select Bguide1 and click Select.
The Bguide1 data set is mapped to the NCA 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.
Dosing regimen
In this example one dose of 55 mg was administered at time 0.
Dosing options are located in the Dose Options area in the Options tab.
• Extravascular is selected by default in the Type menu. Do not change this setting.
Enter the dosing data:
There are two ways to enter dosing data: Enter the dosing data manually or Cre-ate a dosing worksheet.
Enter the dosing data manually
1. Select Dosing in the NCA object's Setup list. The Dosing panel is displayed.
2. Select the Use internal Worksheet check box.
The Dosing sorts dialog is displayed. The Dosing sorts dialog prompts the user to select the sort variables to use to create the internal dosing worksheet.
Dosing sorts dialog
3. Click OK to accept the default sort variable.
4. In the first cell under Dose type 55.
5. In the first cell under Time of Dose type 0.
6. Do not enter any values in the Tau column.
7. Use the pointer to select the first cells under Dose and Time of Dose. The selected cells are highlighted.
8. Place the pointer over the black square on the lower right side of the selec-tion. The pointer changes to the following shape: . This signifies that the drag and fill feature can be used.
9. Press the left mouse button and drag the selection down to fill the Dose and Time of Dose cells beside each subject.
10.In the Dose Options area in the Options tab, type mg in the Unit field.
Dose Options area
11.Go to Terminal elimination phase on page 39.
Create a dosing worksheet
1. Right-click the Data folder in the Object Browser and select New > Work-sheet.
The new worksheet is automatically displayed in the Grid tab.
The Columns tab is located underneath the Grid tab. The Columns tab is used to add columns to a worksheet.
3. Click the Add button underneath the Columns box. The New Column Proper-ties dialog is displayed.
• Use the New Column Properties dialog to define the data type and the name of a new column.
4. Select the Text option button.
5. In the Column Name field type Subject and click OK.
• A new column is displayed in the Columns box and in the Grid tab. Single-click a column header in the Columns box to rename it.
6. In the first cell under Subject, type DW for subject DW and press ENTER.
Repeat for subjects GS and RH.
7. Click the Add button underneath the Columns box.
8. The Numeric option button is selected by default. Do not change this setting.
9. In the Column Name field type Dose and click OK.
10.In the Unit field for the Dose column type mg.
11.In the first cell under Dose type 55.
12.Add a final Numeric column and name it Time_of_Dose.
Note: Newly created columns do not support empty spaces in the column names.
Phoenix can import column names with spaces, but it will not allow users to create column names with spaces.
13.In the first cell under Time_of_Dose type 0.
14.Use the drag and fill feature to fill the rest of the dosing data worksheet by highlighting the first two cells underneath Dose and Time_of_Dose and dragging the selection down.
15.The finished worksheet looks like this:
Map the NCA Dosing Data worksheet to the Dosing panel:
1. Select the NCA object in the Object Browser.
2. Select Dosing in the Setup list.
3. Map the NCA Dosing Data worksheet to the Dosing panel in one of two ways:
• Use the pointer to drag the NCA Dosing Data worksheet from the Data folder to the Dosing panel.
• Click the Select source button in the Dosing panel to select the work-sheet and map it to the Dosing panel.
4. Use the option buttons in the Dosing panel to map Subject to Sort, Dose to Dose, and Time_of_Dose to Time of Dose.
CAUTION: Mapping a worksheet to the Dosing panel overrides the Unit settings in the Dose Options area. If a worksheet is mapped to the Dosing panel make sure that the appropriate units are added to the Dose column in the worksheet.
Terminal elimination phase
Phoenix attempts to estimate the rate constant, , associated with the terminal elimination phase. Although Phoenix is capable of selecting the times to be used in the estimation of , this example provides Phoenix with the time range.
Specify the times to be included:
There are two ways to specify the times to be included.
1. Select Slopes Selector in the Setup list.
2. Select Time Range in the Lambda Z Calculation Method menu.
3. In the Start field type 8.
4. In the End field type 24.
5. Make the same changes for the other subjects by selecting the Subject=GS tab and the Subject=RH tab and entering the same Start and End time val-ues.
OR
1. Select Slopes in the Setup list.
2. In the first cell under Start Time type 8.
Z
Z
5. Use the drag and fill feature to fill the rest of the Slopes worksheet by high-lighting the first two cells under Start Time and End Time and dragging the selection down for all subjects.
6. Select Slopes Selector in the Setup list.
Note that Time Range is selected in the Lambda Z Calculation Method menu.
The Start and End times have been specified for each subject. A line is displayed on each graph that shows the Lambda Z time range.
In this example no points are excluded from the specified Lambda Z time range.
The example Noncompartmental analysis with exclusions, computing partial areas on page 46 demonstrates Lambda Z exclusions.
Therapeutic response
The next step is to define a target concentration range to enable calculation of the time and area located above, below, and within that range.
Note: See Noncompartmental analysis with exclusions, computing partial areas on page 46 for an NCA example that includes computation of partial areas under the curve.
Specify the therapeutic response options:
1. Select Therapeutic Response in the Setup list.
2. Select the Use internal Worksheet check box.
The Therapeutic Response sorts dialog is displayed. The Therapeutic Response sorts dialog prompts the user to select the sort variables to use to create the internal dosing worksheet.
3. Click OK to accept the default sort variable.
4. Select Therapeutic Response in the Setup list.
5. In the Lower cell for each subject type 2.
6. In the Upper cell for each subject type 4.
Units
The next step in setting options is to specify preferred output units. The indepen-dent variable, depenindepen-dent variable, and dosing regimen must have units before preferred output units can be set.
Set preferred units:
1. Select Units in the Setup list.
The Units worksheet lists both the Default units and the Preferred units for each parameter.
2. Select the cell in the Preferred column for Volume (Vz, Vz/F, Vss). The new preferred unit is L (liter).
3. In the Preferred cell for Volume type L.
NCA Model options
Four methods are available for computing the area under the curve. The default method is the linear trapezoidal rule with linear interpolation. This example uses the Linear Log Trapezoidal method: linear trapezoidal rule up to Tmax, and log trapezoidal rule for the remainder of the curve.
Specify the NCA model options:
Use the Options tab to specify settings for the NCA model options. The Options tab is located underneath the Setup tab.
1. Select Linear Log Trapezoidal in the Calculation Method menu.
2. In the Titles field type Example of Noncompartmental Analysis.
Results
At this point, all of the necessary commands have been specified. This example includes text, worksheet, and plot output.
Run the analysis:
• Click the Execute button. The results are displayed on the Results tab.
NCA Text Output
The NCA object’s Core output text file contains user settings, a brief summary table, and final parameters output for each subject.
Core output
NCA worksheet output
The NCA object’s worksheet output contains summary tables of the results.
Subject=DW Number of nonmissing observations: 16
Dose time: 0.00 Dose amount: 55.00
Calculation method: Linear/Log Trapezoidal
Weighting for lambda_z calculations: Uniform weighting
Lambda_z method: User-specified lambda_z range, Log regression User's lambda_z bounds: 8.00, 24.00
Lower bound for therapeutic window: 2.00 Upper bound for therapeutic window: 4.00
Item Contents
Dosing Used The dosing regimen specified in the Dosing panel.
Exclusions Any excluded data points specified in the Slopes panel.
Final Parameters Estimates of the final parameters for each level of the sort vari-able (each subject for this example), including times and areas above (“TimeHgh”), in (“TimeDur”) and below (“TimeLow”) the therapeutic response (AUCHgh, AUCLow, etc.). Parameter names that include “INF” are extrapolated to infinity using esti-mated Lambda Z.
The Final Parameters and the Summary Table results are shown below:
Final Parameters
This subject’s concentrations were within the theoretical therapeutic range for just over 13.8 hours, as reflected in the parameter TimeDur.
Final Parameters Pivoted
The same as Final Parameters, but with one parameter per col-umn, in order to conveniently perform further analysis on indi-vidual parameters.
Partial Areas Lists start and end times used to define the partial areas under the curve.
Plot Titles The title of each graph in the output.
Slopes Settings The settings for the user specified for the Terminal elimination phase.
Summary Table The sort variables, X variable, points included in the regression for Lambda Z (noted with *), Y variable, predicted Y for the regression, residual for the regression, area under the curve (AUC), area under the moment curve AUMC and the Weight used for the regression.
Item Contents
Summary Table
NCA plot output
The NCA object’s plot output displays Observed Y and Predicted Y vs X graphs for each subject.
Descriptive statistics
At this point, it is convenient to summarize the results of the noncompartmental analysis using a Descriptive Stats object. This example summarizes parameter estimates across subjects.
Summarize the Final Parameters results:
1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Descriptive Stats.
The Descriptive Stats object is added to the workflow in the Object Browser.
2. Map the NCA Final Parameters worksheet as the input source for the Descriptive Stats object:
• In the Descriptive Stats Main Mappings panel click the Select Source button to open the Select Object dialog.
• Select the NCA Final Parameters worksheet and click Select.
OR
• Select the workflow. The workflow Diagram tab is displayed in the right viewing panel.
Each operational object in a workflow is represented in the Diagram tab.
• Click the Down Arrows buttons to expand the NCA and Descriptive Stats symbols.
Each operational object in the Diagram tab contains a complete list of all input and output sources.
• Click the (+) symbol beside the NCA Results.
• Click the (+) symbol beside the Descriptive Stats Inputs.
• Drag the NCA Final Parameters worksheet to the Descriptive Stats Main input.
The Final Parameters worksheet is mapped to the Descriptive Stats object.
A line is displayed that represents the mapping between the NCA and Descriptive Stats objects.
3. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:
• Leave Subject mapped to None.
• Map Parameter to the Sort context.
• Map Estimate to the Summary context.
Note: Mapping Parameter to Sort computes statistics on the parameter estimates and mapping Estimate to Summary computes one statistic per parameter.
Descriptive Stats options are accessible in the Options tab, which is located underneath the Setup tab.
4. Select the Confidence Interval check box. The default setting for the Confi-dence Interval is 95%. Do not change this setting.
5. Select the Number of SD check box. The default setting for the number of standard deviations is 1. Do not change this setting.
6. Click the Execute button. The results are displayed on the Results tab.
The three subjects spent an average of 13.6 hours within the therapeutic concen-tration range, as shown by the parameter TimeDur.