Phoenix WinNonlin 6.3 Examples Guide

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Phoenix® WinNonlin® 6.3

Phoenix® Connect 1.3

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Chapter 1 Analyzing Multiple Profiles . . . .1

Preparing the data . . . 1

Reviewing profile plots . . . 2

Noncompartmental analysis . . . 5

NCA model variables . . . 5

Dosing regimen . . . 6

Model options . . . 9

Results . . . 9

Summarizing the output . . . 11

Exporting results to Microsoft Word . . . 14

Chapter 2 Plots . . . .17

Error bar plots . . . 17

Set up the data . . . 17

Descriptive statistics . . . 19

Plot the mean +/- standard deviation using relative error bars . . . 21

Plot the median, minimum and maximum using absolute error bars . . . 23

Overlay multiple plots. . . 25

Overlaying variables from the same data set . . . 26

Overlaying variables from multiple data sets . . . 28

Chapter 3 Noncompartmental Analysis . . . .33

A noncompartmental analysis of three profiles . . . 33

The data . . . 33

The model . . . 35

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Noncompartmental analysis with exclusions, computing partial areas . . . 46

Model settings . . . 47

Results . . . 49

Additional NCA examples. . . 51

NCA_PD.pmo . . . 52

SparseSamplingChaioYeh.pmo . . . 53

Urine.pmo . . . 53

Chapter 4 Workflows and Templates . . . .55

Create a workflow . . . 57

Create the formulation data set for the bioequivalence model . . . 68

Create and add a template . . . 71

Chapter 5 Pharmacokinetic Modeling . . . .79

Exploring the data . . . 79

Plot the time and concentration data . . . 80

Set up the model . . . 81

Dosing regimen . . . 81

Initial parameter estimates . . . 83

Run the model and view the results. . . 84

Saving the project and the results . . . 89

Chapter 6 The Phoenix Toolbox . . . .95

Semicompartmental modeling . . . 95

Set up semicompartmental modeling . . . 98

Output . . . 99

Pharmacodynamic modeling. . . 102

Results . . . 104

Nonparametric superposition. . . 105

Results . . . 106

Output for effect-site concentrations. . . 108

Steady-state effect computation . . . 108

Crossover design . . . 112

Data stacked in one column . . . 112

Data in separate columns . . . 114

Deconvolution . . . 116

Absolute bioavailability . . . 117

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Chapter 7 Linear Mixed Effects Modeling . . . .123

Comparing treatment groups. . . 123

The model . . . 123

Results . . . 126

An illustration of variance structures . . . 127

The model . . . 127

Results . . . 129

Re-execute the model with new data . . . 130

Chapter 8 The IVIVC Workflow . . . .133

Setting up the data. . . 133

Selecting and smoothing the dissolution data . . . 135

Fitting the unit impulse response and estimating absorption . . . 138

Developing and validating the IVIVC model . . . 140

Predicting PK . . . 141

Chapter 9 Tables . . . .145

Final Parameters table . . . 145

Table Type 3. . . 145

Select and format summary statistics . . . 148

Joining raw data and modeling output . . . 150

Recreating WinNonlin’s table template 9 in Phoenix . . . 151

Summary statistics . . . 154

Using custom tables . . . 156

Chapter 10 Simulation and Study Design . . . .159

Using Phoenix as an aid in designing experiments. . . 159

Comparison of two designs . . . 159

The data set. . . 160

Insert and map the PK model . . . 161

Enter the dosing data . . . 162

Model parameters and simulation . . . 163

Enter the initial estimates: . . . 163

Results . . . 164

Designing the sampling plan . . . 164

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Average bioequivalence . . . 167

Calculating average bioequivalence . . . 167

Results . . . 170

A replicated crossover design . . . 170

Calculating average bioequivalence . . . 171

Results . . . 173

Individual and population bioequivalence. . . 174

The population/individual model . . . 175

The model . . . 175

Results . . . 177

Comparing average bioequivalence . . . 177

Chapter 12 Transformations . . . .181

Computing ratios . . . 181

Create the project and import the data . . . 181

Merge the two data sets. . . 182

Calculate F (fraction of oral dose absorbed): . . . 184

Calculate descriptive statistics . . . 185

Creating a baseline-adjusted variable . . . 186

Import the data set. . . 186

Compute the change from baseline using a column transform . . . 186

Chapter 13 Modeling Examples . . . .189

Load, view, and run the example models . . . 189

Pharmacokinetic model . . . 190

Pharmacokinetic model with multiple doses . . . 190

Probit analysis: maximum likelihood estimation of potency . . . 190

Logit regression (bioassay) . . . 191

Survival analysis . . . 192

System of two differential equations with data for both compartments . . . 193

System of two differential equations with data on one compartment . . . 193

Multiple linear regression . . . 193

Cumulative areas under the curve . . . 194

Mitscherlich nonlinear model . . . 194

Four parameter logistic model . . . 195

Linear regression . . . 195

Indirect response model. . . 195

Ke0 link model . . . 196

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Analyzing Multiple Profiles

A start-to-finish example using noncompartmental

analysis

This example demonstrates the general steps to summarize a data set using noncompartmental analysis. The data set contains time-concentration profiles from a two period crossover study with six subjects. See Chapter 3 on page 33 for additional examples of noncompartmental analysis.

Preparing the data

Data for noncompartmental analyses can include one or more sort variables. Sort variables have discrete values that identify time-concentration profiles to be ana-lyzed individually. Input data sets should be stacked (long and skinny) rather than unstacked (short and wide).

Stacking simply means moving information stored in column headings into the rows. For example, matrix data such as plasma or urine can be placed in one row, and all associated data are arranged in rows beside the matrix data. This means that all measurements appear in a single column, with one or more addi-tional columns flagging which data belong to which matrix. The data for one matrix must be listed first, then all the data for the other matrix.

For noncompartmental analysis data, this means that time (the independent vari-able) and concentration (the dependent varivari-able) data for all individuals should occupy only one column each, with one or more additional columns (sort vari-ables) used to identify individual profiles.

The study data for this example are contained in Profiles.CSV, which is located in the Phoenix examples directory. This crossover study includes two sort variables: Subject (subject identifiers) and Form (formulation). There are six subjects, each of whom was tested with two formulations, for a total of twelve profiles.

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Start Phoenix and create a new project:

1. In the Windows Start menu, select All Programs > Pharsight > Phoenix > Phoenix to start Phoenix.

2. Select File > New Project to create a new project. A new project is created in the Object Browser.

3. Name the new project Multiple Profiles.

Import the data:

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 Profiles.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. Select the Has units row check box.

5. Click Finish. The data set is added to the project’s Data folder.

A data set in CSV (Comma Separated Values) format is added to the Data folder as a worksheet.

6. 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 the worksheet in its own window, select the worksheet and double-click or press ENTER. The data set is displayed in a worksheet window.

Reviewing profile plots

Before analyzing the data, examine a plot of each profile to confirm the model and scan for outlying data points.

Insert the XY Plot object:

1. Select the workflow object in the Object Browser and then select Insert > Plotting > XY Plot.

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Note: The XY Plot object can also be added by right-clicking the workflow object and selecting New > Plotting > XY Plot. Any object can be added by select-ing New in the workflow object menu.

The XY Plot object is added to the workflow in the Object Browser. » Objects automatically open in the right viewing panel when they are

inserted into a workflow.

» Each object’s default view is the Setup tab, which contains all the steps necessary to set up an object.

» To view the plot in its own window, double-click the XY Plot object in the Object Browser or select the plot object and press ENTER. The XY Plot window is displayed.

» The same set of instructions can be used to set up an operational object if it is displayed in the right viewing panel or in its own window.

2. Map the data set Profiles as the input source for the XY Plot object:

• Use the pointer to drag the Profiles worksheet from the Data folder to the XY Data Mappings panel.

OR

• In the XY Plot XY Data Mappings panel click the Select source button to open the Select Object dialog.

• Click the (+) signs beside Multiple Profiles > Data to expand the menu tree.

• Select the Profiles worksheet and click Select. The Profiles data set is mapped to the XY Plot.

3. Use the option buttons in the XY Data Mappings panel to map the data types to the following contexts:

• Map Subject to the Group context.

• Map Form to the Lattice Conditions Page (Sort) context. • Map Time to the X context.

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Set plot options:

The plot display options are located in the XY Plot's Options tab. Expand items in the Options menu tree by clicking the (+) signs.

• Select Plot > Title. In the Title field type Plotting Multiple Pro-files.

• Accept all other default entries for the XY Plot options.

Execute the plot:

1. Click the Execute button. The Results are displayed on the Results tab.

2. If the XY Plot is opened in its own window, close the window. Return to the window at any time by selecting the XY Plot object in the Object Browser and double-clicking or pressing ENTER.

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Noncompartmental analysis

The noncompartmental analysis (NCA) plasma model 200 (extravascular dosing) is suitable for this data. All subjects had a dose of 100 ng at time 0 for each for-mulation. All profiles use uniform weighting, and allow Phoenix to select the ter-minal elimination phase. The linear trapezoidal method with linear interpolation is used to compute the areas under the curve.

Insert the NCA object:

1. Select the workflow object in the Object Browser and then select Insert > NCA and Toolbox > NCA.

The NCA object is added to the workflow object in the Object Browser.

Note: To view the object in its own window double-click the NCA object or select the NCA object and press ENTER. The NCA window is displayed.

2. Map the data set Profiles as the input source for the NCA object:

• Use the pointer to drag the Profiles worksheet from the Data folder to the Main Mappings panel.

OR

• In the NCA Main Mappings panel click the Select source button to open the Select Object dialog.

• Click the (+) signs beside Multiple Profiles > Data to expand the menu tree.

• Select the Profiles worksheet and click Select. The Profiles data set is mapped to the NCA object.

NCA model variables

Map the model variables:

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 Form to the Sort context.

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Dosing regimen

In this example one dose of 100 ng was administered at time 0 for each subject and formulation.

• 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 variables.

4. In the first cell under Dose type 100.

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.

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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 and formulation.

10.In the Dose Options area in the Options tab, type ng in the Unit field. Dose Options area

11.Go to Model options on page 9.

Create a dosing worksheet

1. Right-click the Data folder in the Object Browser and select New > Work-sheet.

2. Name the new worksheet NCA Dosing Data.

The new worksheet is automatically displayed in the Grid tab.

Note: To view the worksheet in its own window, select the worksheet and double-click or press ENTER. The data set is displayed in a worksheet window. 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.

» The Numeric option button is selected by default. Do not change this set-ting.

4. 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.

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7. In the Column Name field type Dose and click OK.

8. In the Unit field for the Dose column type ng.

10.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 does not allow users to create column names with spaces.

11.In the first cell under Time_of_Dose type 0.

12.Use the drag and fill feature (see step 8. under Enter the dosing data manu-ally) 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.

13.The finished worksheet looks like this:

14.If the NCA Dosing Data worksheet is opened in its own window, close the window. Return to the window at any time by selecting the worksheet in the Data folder and double-clicking or pressing ENTER.

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.

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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.

Model options

Use the Options tab to specify settings for the NCA model options. The Options tab is located underneath the Setup tab.

Model options:

1. The default setting for Model Type is Plasma (200-202). Do not change this setting.

Note: The exact plasma model type (200, 201, or 202) is determined by the dose type.

2. The default setting for Calculation Method is Linear Trapezoidal Linear Interpolation. Do not change this setting.

3. In the Titles field type Processing Multiple Profiles with Model 200.

At this point all of the necessary mappings and options have been specified.

Run the analysis:

1. Click the Execute button. The results are displayed on the Results tab.

2. If the NCA object is opened in its own window, close the window. Return to the window at any time by selecting the NCA object in the Object Browser and double-clicking or pressing ENTER.

Results

The Text Output, the Output Data worksheets, and the Observed Y and Pre-dicted Y vs X plots are located on the Results page.

The worksheet output for noncompartmental analysis includes seven work-sheets: Dosing Used, Exclusions, Final Parameters, Final Parameters Pivoted, Partial Areas, Plot Titles, Slopes Settings, and Summary Table.

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parameter estimates in one column, with another column used to identify the parameters.

Note that in each Results worksheet the sort variables Subject and Form are included as columns in the data grid, and the output is presented for each level of the sort variables. In addition, each output parameter with units has the units in the column header, except for the Final Parameters worksheet, which places units in their own column beside the Parameter column.

The Core output provides a summary of model settings and all output data included in the workbook output. The plots are a plot of observed versus pre-dicted data for each subject. Each plot is displayed on its own page.

Change the number of plots displayed per page:

1. Select the Observed Y and Predicted Y vs X plot in the Results tab and double-click it. The plot is opened in its own window.

2. Select Plot in the Options menu tree. The lattice controls are located on the Content tab.

3. Clear the Bind Lattice to Data check box.

4. Click the up and down arrows in the Lattice Rows box to change the number of rows used to display plots.

5. Click the up and down arrows in the Lattice Columns box to change the number of columns used to display plots.

» Phoenix can display a maximum of 15 latticed rows and 15 latticed col-umns.

» Phoenix cannot display more than 200 charts per page.

» The number of plots that can be displayed per page depends on the moni-tor size and resolution.

» If too many plots are placed on one page the axes labels, legends, and other plot information can be difficult to read.

6. Close the Observed Y and Predicted Y vs X window. Return to the window at any time by selecting the plot in the Results tab and double-clicking it.

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Summarizing the output

Phoenix's Descriptive Stats object is used to summarize several of the output parameters in the Final Parameters Pivoted worksheet. The Descriptive Stats object generates separate statistics for each formulation.

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 Pivoted 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 Final Parameters Pivoted worksheet and click Select. OR

• Select the workflow. The workflow’s Diagram tab is displayed in the right viewing panel.

Note: To view a workflow in its own window, double-click the workflow or select the workflow and press ENTER. The workflow window is displayed.

Each operational object in a workflow is represented in the Diagram tab. • Click the chevron buttons to expand the NCA and Descriptive Stats

sym-bols.

Each object symbol 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 Pivoted worksheet to the Descriptive Stats Main input.

The Final Parameters Pivoted worksheet is mapped to the Descriptive Stats object. A line is displayed that represents the mapping between the NCA and Descriptive Stats objects.

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Diagram tab mappings

3. Select the Descriptive Stats object in the Object Browser.

4. Use the option buttons in the Main Mappings panel to map the data types to the following contexts:

• Map Form to the Sort context.

• Map Tmax, Cmax, and AUCall to the Summary context. • Leave all other data types mapped to None.

Set the Descriptive Stats options and execute the object:

Descriptive Stats options are accessible in the Options tab, which is located underneath the Setup tab.

1. Select the Confidence Interval check box. The default setting for the Confi-dence Interval is 95%. Do not change this setting.

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2. Select the Number of SD check box. The default setting for the number of standard deviations is 1. Do not change this setting.

3. Click the Execute button. The Results are displayed on the Results tab. This example summarizes AUCall, the area under the curve through the last measured value, Cmax, the maximal concentration of drug in the blood, and

Tmax, the time at maximal concentration. A portion of the output is shown below. Descriptive Stats Statistics output:

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4. If the Descriptive Stats object is opened in its own window, close the window.

Exporting results to Microsoft Word

The results of any operational object can be exported to a Microsoft Word docu-ment. This example shows how to format plot output and export it to Microsoft Word. By default plots are exported at a resolution of 1024 by 768 pixels.

1. Select File > Word Export. The Word Export dialog is displayed. Word Export dialog

2. Clear the Multiple Profiles check box to deselect all objects in the project.

Note: Expand items in the Word Export menu tree by clicking the (+) signs.

3. Click the (+) signs beside Workflow > NCA > Results to expand the menu tree.

4. Select the Observed Y and Predicted Y vs X check box.

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6. Click the Options button.

7. Select the Landscape option button in the Orientation area in the Document tab.

8. Clear the Add source line to objects check box.

9. Click Finished.

10.Click the Export button.

Phoenix creates a new Microsoft Word document and exports the selected objects into the document.

11.Save the Word file and exit Microsoft Word.

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.

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Plots

Creating plots, using error bars on XY plots, and

plotting multiple columns on a single plot

This chapter provides an overview of Phoenix’s plotting capabilities through two types of plot examples:

» Error bar plots below demonstrates the use of absolute and relative error bars on XY plots.

» Overlay multiple plots on page 25 plots multiple variables per plot.

Error bar plots

This example uses summary statistics and error bars to create two XY plots: » Plot the mean +/- standard deviation using relative error bars on page 21. » Plot the median, minimum and maximum using absolute error bars on

page 23.

Set up the data

Create a new project:

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Import the data set:

3. Select Bguide2.dat and click Open.

Note: To view the worksheet in its own window, select the worksheet and double-click or press ENTER. The data set is displayed in a worksheet 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 to create plots.

1. Select Bguide2 in the Data folder. The worksheet is displayed in the Grid tab. 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.

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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 when the data sets are exported to disk or a database. Phoenix adds the units to a row beneath the column headers. When importing 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.

16.If the Bguide2 worksheet is opened in its own window, close the window. Return to the window at any time by selecting the Bguide2 worksheet in the Data folder and double-clicking or pressing ENTER.

Descriptive statistics

To create error data for the error bars, this example computes means and stan-dard deviations for the concentration data at each time point.

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Compute summary statistics:

1. Select the workflow object in the Object Browser and then select Insert > NCA and Toolbox > Descriptive Stats.

Note: The Descriptive Stats object can also be added by right-clicking the workflow and selecting New > NCA and Toolbox > Descriptive Stats. Any object can be added by selecting New in the workflow menu.

The Descriptive Stats object is added to the workflow in the Object Browser. » Objects automatically open in the right viewing panel when they are

inserted into a workflow.

» Each object’s default view is the Setup tab, which contains all the steps necessary to set up an object.

• To view the plot in its own window, double-click the Descriptive Stats object or select the plot object and press ENTER. The Descriptive Stats window is displayed.

• The same set of instructions can be used to set up an object if it is dis-played in the right viewing panel or in its own window.

2. Map the data set Bguide2 as the input source for the Descriptive Stats object: • Use the pointer to drag the Bguide2 worksheet from the Data folder to the

Main Mappings panel. OR

• In the Descriptive Stats Main Mappings panel click the Select source button to open the Select Source dialog.

• Select Bguide2 and click OK.

The Bguide2 data set is mapped to the Descriptive Stats object.

• Leave Sex mapped to None. • Leave Subject mapped to None. • Map Time to the Sort context. • Map Conc to the Summary context.

Descriptive Stats options are accessible in the Options tab, which is located underneath the Setup tab.

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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.

7. If the Descriptive Stats object is opened in its own window, close the window. Return to the window at any time by selecting the Descriptive Stats object in the Object Browser and double-clicking or pressing ENTER.

Plot the mean +/- standard deviation using relative error bars

1. Select the workflow object in the Object Browser and then select Insert > Plotting > XY Plot.

The XY Plot object is added to the workflow in the Object Browser.

2. Map the Descriptive Stats Statistics worksheet as the input source for the XY Plot object:

• In the XY Plot XY Data Mappings panel click the Select Source button to open the Select Source dialog.

• Select the Descriptive Stat’s Statistics worksheet and click OK. 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 chevron buttons to expand the Descriptive Stats and XY Plot

objects.

Each operational object in the Diagram tab contains a complete list of all input and output sources.

• Click the (+) symbol beside the Descriptive Stats Results. • Click the (+) symbol beside the XY Plot Inputs.

• Drag the Descriptive Stats Statistics worksheet to the XY Plot’s XY Data input.

The Statistics worksheet is mapped to the XY Plot object. A line is dis-played that represents the mapping between the Descriptive Stats and XY Plot objects.

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Diagram tab mappings

Note: To view the workflow in its own window, double-click the workflow or select the workflow and press ENTER. The workflow window is displayed.

3. Select the XY Plot object in the Object Browser.

• Map Time to the X context. • Map Mean to the Y context.

• Map SD to the Lower and Upper Error Bars. • Leave all other data types mapped to None.

The plot display options are located in the XY Plot's Options tab.

1. Select Plot > Title. In the Title field type: Mean +/- Standard Devia-tion.

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3. User is selected by default in the Error Calculation Type menu. Do not change this setting.

4. Relative is selected by default in the User Calculation Type menu. Do not change this setting.

Using the Relative User Calculation Type causes Phoenix to add and subtract the errors from the mean.

5. Click the Execute button. The results are displayed on the Results tab. Mean +/- Standard Deviation plot

Plot the median, minimum and maximum using absolute error bars

1. Select the workflow in the Object Browser and then select Insert > Plotting > XY Plot.

Note: When multiple objects of the same type are added to a workflow they are numbered sequentially. For example, the second XY Plot object added to this workflow is called XY Plot 1.

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• In the XY Plot 1 XY Data Mappings panel click the Select Source but-ton to open the Select Source dialog.

• Select the Descriptive Stats Statistics worksheet and click OK. OR

Each operational object in a workflow is represented in the Diagram tab. • Click the chevron buttons to expand the Descriptive Stats and XY Plot 1

symbols.

• Click the (+) symbol beside the Descriptive Stats Results. • Click the (+) symbol beside the XY Plot 1 Inputs.

• Drag the Descriptive Stats Statistics worksheet to the XY Plot 1 XY Data input.

The Statistics worksheet is mapped to the XY Plot 1 object. A line is dis-played that represents the mapping between the Descriptive Stats and XY Plot 1 objects.

3. Select the XY Plot 1 object in the Object Browser.

• Map Time to the X context. • Map Median to the Y context. • Map Min to the Lower Error Bar. • Map Max to the Upper Error Bar.

• Leave all other data types mapped to None.

The plot display options are located in the XY Plot 1's Options tab.

1. Select Plot > Title. In the Title field type Minimum, Median, and Maxi-mum Concentrations.

2. Select Graphs > Median vs Time > Error Bars.

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Using the Absolute User Calculation Type instructs Phoenix to plot the Min and Max values on the Y axis, rather than to add and subtract them from the Median.

4. Click the Execute button. The results are displayed on the Results tab. Minimum, Median, and Maximum Concentrations plot

Overlay multiple plots

Overlaid plots can display data for more than one variable on one set of axes. They can be created from separate columns in the same data set, columns in dif-ferent data sets, or both.

• Overlaying variables from the same data set on page 26 overlays data from separate columns in the same workbook.

• Overlaying variables from multiple data sets on page 28 overlays variables from different workbooks.

Note: It is also possible to create similar plots without using the overlay feature, if the data are stored in one column, by assigning a variable or parameter to the Group context.

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Overlaying variables from the same data set

This example plots the summary statistics for concentration at each time interval.

Plot summary statistics for concentration at each time point:

Note: The XY Plot object can also be added by right-clicking the workflow and selecting New > Plotting > XY Plot.

The XY Plot object is added to the workflow in the Object Browser. The new XY Plot object is called XY Plot 2.

2. Map the Descriptive Stats Statistics worksheet as the input source for the XY Plot 2 object:

• In the XY Plot 2 XY Data Mappings panel click the Select Source but-ton to open the Select Source dialog.

• Select the Descriptive Stats Statistics worksheet and click OK. OR

Each operational object in a workflow is represented in the Diagram tab. • Click the chevron buttons to expand the Descriptive Stats and XY Plot 2

symbols.

• Click the (+) symbol beside the Descriptive Stats Results. • Click the (+) symbol beside the XY Plot 2 Inputs.

• Drag the Descriptive Stats Statistics worksheet to the XY Plot 2 XY Data input.

The Statistics worksheet is mapped to the XY Plot object. A line is dis-played that represents the mapping between the Descriptive Stats and XY Plot 2 objects.

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• Map Time to the X context.

• Map CI 95% Lower Mean to the Y context. • Map CI 95% Upper Mean to the Y2 context. • Leave all other data types mapped to None.

The plot display options are located in the XY Plot 2's Options tab. Expand items in the Options menu tree by clicking the (+) signs.

1. Select Plot > Title. In the Title field type Overlay Charts. Press ENTER to move to the next line and type: Example 1.

2. Select Axes > Y. Select the Label tab. In the Label field type Confidence Interval.

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Overlaying variables from multiple data sets

This example will plot the Observed and Predicted concentrations from a model fitting by using the output from Bg1.pmo.

Import the data sets and the PK model:

2. Navigate to the Phoenix legacy WinNonlin examples subdirectory, which by default is located at C:\Program

Files\Pharsight\Phoe-nix\application\Examples\Legacy WinNonlin.

3. Select Bg1.pmo and click Open.

The Data Import Wizard is displayed. The wizard is used to assign options for how the data are imported and presented.

Note: PMO files can only be loaded on 32-bit operating systems or using the Phoenix32.exe on 64-bit operating systems.

A file in PMO (Pharsight Model Object) format is added to the Data folder as one or more workbook objects. A .pmo file also adds one or more operational objects to the workflow.

The Bg1.pmo file adds:

• A data set in workbook form (bg1). • Dosing worksheet (Bg1_sources). • A PK Model object named Bg1.

5. Click the (+) symbols beside bg1 and Bg1_sources in the Data folder to view the data sets’ worksheets.

Run the PK Model:

1. Select the PK Model object Bg1 in the Object Browser. The PK Model’s Setup tab is displayed in the right viewing panel.

CAUTION: Models saved in PMO format contain all the necessary data mappings and option settings. Do not change these settings.

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2. Select items in the PK Model object’s Setup tab list to examine the model’s data mappings and option settings.

The imported PK Model object uses PK Model 3, which is a one compartment model with 1st order absorption.

3. Click the Execute button. The results are displayed on the Results tab. There are now two data sets available: the source data set bg1 and the PK Model’s Summary Table results. Both data sets are used to create the overlay plot.

Add the first XY Plot plot:

2. Map the data set bg1 as the input source for the XY Plot 3 object:

• Use the pointer to drag the bg1 Sheet1 worksheet from the Data folder to the XY Data Mappings panel.

OR

• In the XY Plot 3 XY Data Mappings panel click the Select source but-ton to open the Select Object dialog.

• Select the bg1 Sheet1 worksheet and click Select. The bg1 data set is mapped to the XY Plot 3 object.

• Leave Subject mapped to None. • Map Time to the X context. • Map Conc to the Y context.

Add the second XY Plot plot:

1. Select Plot in the Options tab menu tree. Select the Graphs tab.

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Graphs tab

A second XY Plot input named XY 1 Data is added to the Setup list.

3. Map the PK Model Summary Table worksheet as the input source for the second XY Plot:

• In the XY Plot 3 XY 1 Data Mappings panel click the Select Source button to open the Select Object dialog.

• Select the Bg1 Summary Table worksheet and click Select. OR

Each operational object in a workflow is represented in the Diagram tab. • Click the chevron buttons to expand the Bg1 and XY Plot 3 symbols.

• Click the (+) symbol beside the Bg1 Results. • Click the (+) symbol beside the XY Plot 3 Inputs.

• Drag the Bg1 Summary Table worksheet to the XY Plot 3 XY 1 Data input. The Summary Table worksheet is mapped to the second XY Plot. A line is displayed that represents the mapping between the Bg1 and XY Plot 3 objects.

4. Use the option buttons in the XY 1 Data Mappings panel to map the data types to the following contexts:

• Map Time to the X context. • Map Predicted to the Y context.

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Note: To delete a plot, select Plot in the Options menu tree and select the Graphs tab. Select the plot to be deleted and click Remove.

Set graph options:

The graph display options are located in the XY Plot's Options tab. Expand items in the Options menu tree by clicking the (+) signs.

1. Select Plot > Title. In the Title field type: Overlay Charts 2. Press ENTER to move to the next line and type: Example using two data sets.

2. Select Graphs > Conc vs Time. Select the Appearance tab.

3. In the Appearance tab, use the Marker Color menu to change the marker color to red.

4. Click the Execute button. Both XY Plot graphs are displayed together in the Results tab.

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

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Noncompartmental

Analysis

Computing areas, slopes, and moments

This chapter includes the following examples of noncompartmental analysis: » A noncompartmental analysis of three profiles on page 33.

» 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:

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Import the data set:

3. Select Bguide1.dat and click Open.

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.

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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.

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• 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.

• 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.

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.

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Dosing sorts dialog

3. Click OK to accept the default sort variable.

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.

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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.

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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

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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.

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.

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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:

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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

Date: 4/10/2009 Time: 17:01:42 Example of Noncompartmental Analysis

WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 6.3.0.326

Core Version 04Jun2007 Settings

---Model: Plasma Data, Extravascular Administration 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.

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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.

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Summary Table

NCA plot output

The NCA object’s plot output displays Observed Y and Predicted Y vs X graphs for each subject.

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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

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.

• 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.

• Leave Subject mapped to None. • Map Parameter to the Sort context.