Medios para alcanzar la virtud de la castidad

This section uses the NonParametric Superposition object to predict plasma con-centrations and effect-site concon-centrations at steady-state based on single-dose data. This feature allows for predictions on data that are otherwise difficult to model.

This example uses the output from the semicompartmental modeling example, detailed under Semicompartmental modeling on page 95.

Estimate steady-state plasma concentrations using nonparametric superposition:

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

The NonParametric Superposition object is added to the workflow in the Object Browser.

2. Map the SemiCompartmental Results worksheet as the input source for the NonParametric Superposition object:

• In the NonParametric Main Mappings panel click the Select Source button to open the Select Object dialog.

• Select the SemiCompartmental Results 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 chevron buttons to expand the SemiCompartmental and Non-Parametric symbols.

Each object symbol contains a complete list of all input and output sources.

• Click the (+) symbol beside the SemiCompartmental Results.

• Click the (+) symbol beside the NonParametric Inputs.

• Drag the SemiCompartmental Results worksheet to the NonParametric Main input.

The Results worksheet is mapped to the NonParametric object. A line is displayed that represents the mapping between the SemiCompartmental and NonParametric objects.

3. Use the option buttons in the NonParametric object’s 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 Ce mapped to None.

• Leave Effect mapped to None.

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

4. In the Options tab, type 50 in the Loading dose field.

5. In the Maintenance dose field type 50.

6. In the Tau (dosing interval) field type 4.

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

Results

Worksheet

The NonParametric worksheet results provide predicted steady-state plasma concentrations and Lambda Z and half-life estimates.

Graph

The graph output shows predicted steady state concentrations over time for each subject. The first subject’s graph is shown below.

Estimate steady-state effect-site concentrations using nonparametric superposition:

1. Use the option buttons in the NonParametric object’s Main Mappings panel to re-map the data types to the following contexts:

• Leave Subject mapped to the Sort context.

• Leave Time mapped to the Time context.

• Map Conc to None.

• Map Ce to the Concentration context.

• Leave Effect mapped to None.

2. Select the NonParametric object’s Terminal Phase panel.

3. Select the Use internal Worksheet check box.

4. In the Start column for the first subject, type 4. In the End column, type 8.

Repeat for the other two subjects.

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

Output for effect-site concentrations

The new NonParametric worksheet results provide predicted effect site concen-trations at steady-state and Lambda Z and half-life estimates.

The plot output shows predicted effect site concentrations at steady-state over time for each subject. The first subject’s graph is shown below.

Now it is possible to compute the state effect from the predicted steady-state concentrations at the effect site.

Steady-state effect computation

Skip this section and proceed to Crossover design on page 112 if Microsoft Excel XP to 2007 is not installed on the same machine as Phoenix.

Compute steady-state effects:

1. Select the PD Model object in the Object Browser.

• The sample graph for PD model 103 is displayed in the Model Selection tab. Note the effect formula for model 103 is E=E0*(1-(C/(C+IC50))).

2. Select the NonParametric object in the Object Browser. Select the NonPara-metric object’s Results tab.

3. Right-click the Concentrations (effect site concentrations) worksheet and select Copy to Data Folder.

The Concentrations worksheet is added to the project’s Data folder and renamed Concentrations from NonParametric.

4. Select Concentrations from NonParametric in the Data folder. The work-sheet 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 add columns to a worksheet or edit existing columns.

5. 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.

6. The Numeric option button is selected by default. Do not change this setting.

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

8. The new column is displayed in the Columns box and in the Grid tab.

9. Use the Down Arrow button beside the Columns box to move the Effect column header to the bottom of the Columns list.

10.Right-click Concentrations from NonParametric and select Edit in Excel.

Phoenix displays the following message warning users that changes made in Excel are not recorded in Phoenix.

11.Click OK.

The worksheet is opened in Excel.

12.In the Concentrations from NonParametric worksheet enter the PD model 103 effect formula in the Effect column for each subject at time zero. Use the E0 and IC50 values from the PD Model object’s Final Parameters worksheet.

13.Select the cell in the Effect column at time zero for the first subject, JDW.

14.Type the effect formula shown below in the Effect column cell at time 0 (zero) for subject JDW.

= 102.93*(1-(C3/(C3+0.09))) (for subject JDW) 15.Repeat for the second and third subjects, LEJ and SCC.

= 100.17*(1-(C103/(C103+0.09))) (for subject LEJ)

= 100.45*(1-(C203/(C203+0.08))) (for subject SCC) 16.After the Effect value formula is set up at time zero for each subject copy the

formula to the other time points for each subject.

Excel XP and 2003 users:

• In Excel, select File > Save. Click Save in the Save As dialog.

Because of the way Phoenix handles its interactions with Excel, users can-not use the Save As option in Excel to save the worksheet with a different name or to a different location. The Save option must be used.

• Close Excel and click Yes to save the worksheet.

The Apply Changes message is displayed.

• Click Yes to apply the changes. An entry is written in the worksheet’s His-tory tab noting that it was edited in Excel.

The Save Excel Formulas message is displayed.

• Click Yes to save formulas. The worksheet is no longer editable in Phoenix, but it can be edited in Excel.

– The worksheet can still be used with operational objects.

The changes are applied to the worksheet in Phoenix.

Excel 2007 and 2010 users:

• Click the Office button and select Save.

• Close Excel. Be sure to save the worksheet before closing Excel, or all changes are lost.

The Apply Changes message is displayed.

• Click Yes to apply the changes. An entry is written in the worksheet’s His-tory tab noting that it was edited in Excel.

The Save Excel Formulas message is displayed.

• Click Yes to save formulas. The worksheet is no longer editable in Phoenix, but it can be edited in Excel.

The changes are applied to the worksheet in Phoenix.

The Concentrations from NonParametric worksheet now has Effect values derived from the equations used in the Excel edit.

Once the steady-state effects and concentrations are generated it is possible to use the modified Concentrations from NonParametric worksheet to plot Time vs.

Effect for each subject by mapping the worksheet to an XY Plot object.

• Insert a new XY Plot object. Map Concentrations from NonParametric to the plot object.

• Map Subject to Group, Time to X, and Effect to Y. Leave Ce mapped to None.

Time vs. Effect plot