Select the correlation model to use to fit fraction absorbed (Fabs).
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Choose the correlation model to use to fit the fraction absorbed (Fabs).
If the User Specified option button is selected, then the Correlation.Correlation.WNL ASCII Format panel is made available in the Setup tab, where a correlation model can be entered using the ASCII modeling language.
a. Press Check Syntax to verify the ASCII code entered.
b. In the # parameters menu, select the number of model parameters.
In the Tcutoff field (optional), enter the in vivo time at which the dissolution and absorption will stop increasing.
For the built-in Correlation models, enter “Tvivo” at which the “Diss” function stops increasing and, therefore, the “Fabs” function also stops increasing. In other words, if Tvivo > Tcutoff, then Diss (Tvivo)=Diss(Tcutoff) and Fabs(Tvivo)=Fabs(Tcutoff).
Select an initial value option for correlation model parameters from the first menu near the top of the tab.
User Supplied Initial Parameter Values: Select to enter initial parameter estimates in the Correlation Estimates panel.
WinNonlin Generated Initial Parameter Values: Select to have Phoenix determine the initial parameter values.
Select a boundary option for correlation model parameters from the second menu.
User Supplied Bounds: Select to enter lower and upper bounds for each parameter estimate. Enter the boundary values in the Lower and Upper columns in the Correlation Estimates panel.
Phoenix bounds: Select to have Phoenix generate the lower and upper bounds for each parameter.
Do Not Use Bounds: Select to not apply boundaries to parameter estimates.
Press Build Correlation to run the correlation model.
Press OK in the completion popup.
1. Select the type of area under the curve computation to perform during the validation process from the AUC menu.
AUClast: dose time through the last positive concentration value (AUClast)
AUCall: from dose time through the final observation time (AUCall)
AUCINF_obs: AUClast+Clast/Lambda Z, where Clast is the last observed concentration (AUCINF_obs)
AUCINF_pred: AUClast+Clast/Lambda Z, where Clast is the last predicted concentration (AUCINF)
2. From the Calculation Method menu, select an AUC calculation method.
All methods reduce to the log trapezoidal rule, the linear trapezoidal rule, or both. See “Partial area calculation” in the NCA section for descriptive equations of the calculation methods. (Note that the interpolation options of the AUC calculation methods have no bearing on the validation calculations because partial areas are not computed.)
Linear_Log_Trapezoidal: Uses the log trapezoidal rule after Cmax, or after C0 for IV bolus if C0 > Cmax. Otherwise, the linear trapezoidal rule is used. If Cmax is not unique, then the first maximum is used. This method uses linear trapezoids before Tmax and log trapezoids after Tmax.
Linear_Trapezoidal_Linear_Interpolation: Applies the linear trapezoidal rule to each pair of consecutive points in the dataset that have non-missing values and sums up these areas. This method uses linear trapezoids before and after Tmax.
Linear_Up_Log_Down: The linear trapezoidal rule is used any time that the concentration data is increasing, and the logarithmic trapezoidal rule is used any time that the concentration data is decreasing. This method uses linear trapezoids up and logarithmic trapezoids down before Tmax and linear trapezoids up and logarithmic trapezoids down after Tmax.
The Linear_Log_Trapezoidal and Linear_Up_Log_Down methods apply the same exceptions in area calculation. If a Y value (concentration, rate, or effect) is less than or equal to zero, Phoenix defaults to the linear trapezoidal rule for that point. If adjacent Y values are equal to each other, Phoenix defaults to the linear trapezoidal rule.
3. From the Averaging menu, select Mean to generate arithmetic means or GeoMean to generate geometric means.
4. Press Validation Correlation to generate a table of prediction errors for AUC and Cmax
Press OK in the completion popup.
A worksheet called Validation.Validation Errors is created in the Results tab that contains prediction errors for AUC and Cmax. The %PE column in the Validation.Validation Errors worksheet represents the prediction error percentage.
Prediction error percentage is calculated as %PE (prediction error)=(Predicted-Observed) / Observed x 100%.
For the Avg Internal formulation, the average is taken over the absolute values of PE for the formulations specified as Internal.
Two diagnostic plots can be generated that can help with selecting a correlation model.
1. Select the checkbox beside a plot to include it in the results.
To see a final correlation plot rather than a preliminary diagnostic plot, view the Correlation.Abs vs Diss.Corr Overlay plot after completing the Build Correlation step.
Tvivo vs. Tvitro (Levy) is a Levy plot of in vitro versus in vivo times for a given fraction that is absorbed or dissolved (Levy Plot.Tvivo vs Tvitro).
Fabs vs. Fdiss is a plot of fraction absorbed vs. fraction dissolved at corresponding times, sorted by formulation (Levy Plots.Fabs vs Fdiss)
Include External Formulations, when checked includes the formulations mapped to External in the InVitro Formulation mapping panel.
2. Press Generate Plots to create the plots.
Press OK in the completion popup.
The default for the regression line in the Levy plot is to fix the intercept at the origin. To calculate the intercept, do the following:
3. From the Results tab, double-click the Levy Plot to display it as a separate window.
4. In the tree view, select Graphs > Levy Plot > Regression.
5. Uncheck the Fix intercept at origin box.
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