The InVivo tab includes settings to identify time-concentration or absorption data, formulations, and dosages. Use this tab to fit a unit impulse response (UIR) function to reference concentration data, and/or to deconvolve an existing UIR function and concentration data in order to estimate the fraction of drug absorbed over time.
Generating UIR function and deconvolving data
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The IVIVC object can compute UIRs for all profiles based on the selected reference formulation. It fits a polyexponential function to each profile and chooses the one with the best fit based on either AIC or Weighted SSR.
From the Maximum number of UIR exponentials menu, select the number of exponentials to use in the UIR function.
From the Model Selection menu, select whether to use AIC or Weighted SSR in the UIR function.
From the Weighting menu, select one of five methods for weighting data during modeling (See “Weighting” in the NCA section for explanations of the various schemes).
Uniform Weighting
1/Y (weight by 1/observed Y)
1/Yhat (weight by 1/predicted Y [iterative reweighting])
1/(Y*Y) (weight by 1/observed Y2)
1(Yhat*Yhat) (weight by 1/predicted Y2 [iterative reweighting])
If oral reference formulation and data type is selected in the Formulation Information area, then the Include Time Lag and Strip Ka checkboxes are made available.
Check the Time Lag box to include a lag time parameter in the UIR model.
Check the Strip Ka box to generate the polyexponential describing the IV bolus pharmacokinetics.
This assumes that absorption is truly first-order, fits a model that is n-compartment polyexponential, and convolved with first-order absorption. The absorption is mathematically separated from the decay. If unchecked, then the UIR is a polyexponential model of the reference data.
Check the Use Observed Times for Deconvolution box to create deconvolved data points (fraction absorbed) only at the times at which observations are recorded in the In Vivo dataset.
If unchecked, the deconvolution output will include the number of points specified in the Options tab, listed from initial to final observed sample times.
In this area, select the reference formulation and data type.
1. From the Reference Formulation menu select the formulation identifier to be used in computing the UIR and in building IVIVC models.
The reference formulation must use all oral, IV bolus, or IV infusion input. The IVIVC object does not support combinations of inputs for UIR calculation.
2. From the Reference Data Type menu, select whether the reference input is oral, IV bolus, or IV infusion.
3. In the Dosing Units field, type the dosing units to use with the PK data or click the […] button to use the Units Builder dialog to add dosing units.
See “Using the Units Builder” in the Common Tasks section for more details on this tool.
Note: When using an external worksheet for in vivo dosing data, map the worksheet before using the Dosing Units field. If a unit is entered in the field first that is different from the one in the worksheet, the unit used for the Prediction Dosing data will not get updated correctly. If this happens, re-enter the information in the Prediction Dosing internal worksheet.
In this area, choose from three averaging options for observed or in vivo data.
Generate mean profiles (validate against mean profiles)
The default option and the one that is an accepted approach in regulatory review. When the in vivo dataset contains multiple subjects per formulation selecting this option creates a mean profile for each formulation. The mean profile is used for validation purposes, but not for model building.
From the Averaging menu, select Mean to generate arithmetic means or GeoMean to generate geometric means.
Changing the averaging method used to validate mean profiles affects the Generate UIR, Validate Correlation, and Predict PK processes. It does not affect the Deconvolution or Build Correlation processes, because the mean profile is only used for validation.
Do not generate mean profiles (validate against individuals’ profiles)
With this option, the AUClast and Cmax values over the predicted and observed individual profiles are averaged and then the %PE is calculated based on those averages. This averaging option is not an accepted approach in regulatory review. However, it could be useful when performing exploratory analysis or model building.
Data already deconvolved and averaged
If the selected input dataset has already been deconvolved and averaged, choose this option to have Phoenix skip these steps. No UIR generation, deconvolution, or averaging is performed on the input dataset. Data that is already deconvolved and averaged is validated against individual profiles.
Sort keys (such as subject or study ID) must be included in the datasets mapped to the InVivo Data mapping panel and UIR mapping panel, even if only mean data is used. If no sort column exists in those datasets, one must be added containing the UIR parameters that are used with the corresponding plasma profile. For example, if only one UIR function is used for all formulations, then a sort column containing the parameter A1 must be added to the in vivo and UIR datasets.
Selecting the Data already deconvolved and averaged option causes the following four actions to occur:
Phoenix displays a message warning that any current deconvolution output in the IVIVC project will be removed:
UIR mapping panel and InVivo Fit mapping panel are made available in the Setup tab.
All of the UIR options become unavailable.
The Vivo.Fa_Avg and Vivo.Fa_Avg By Profile plots are not created. If they already exist in the IVIVC results, they are removed.
Note: If any IVIVC operations are dependent on deconvolved and averaged data and the averaging option is changed, then the IVIVC process that contains the dependent operation turns yellow in the Status panel.
Changing any of the In Vivo Data options after the Validate Correlation step is performed, results in a warning message that mean profile information will be removed from the project.
Generating UIR function and deconvolving data
1. When all InVivo tab settings are ready, press Generate UIR to fit the unit impulse response function(s) and generate the in vivo worksheet and plot results.
Press OK in the completion popup.
Note: If the UIR step should fail due to incorrect column mappings (e.g., the Sort and Values columns were inadvertently switched), the Validate Correlation and Predict PK steps will continue to fail, even after the InVivo Data mappings are corrected. Make a copy of the in vivo dataset, add a prefix to all column names (e.g., change the “Time” column to “XTime”), then map this dataset to the InVivo Data setup and map columns appropriately. The Validate Correlation and Predict PK steps will now execute successfully.
2. Press Deconvolve to compute the fraction absorbed over time and to perform numeric deconvolution. (
Press OK in the completion popup.
The IVIVC object uses the specified subject and formulation sort keys to determine individual profiles to deconvolve, using the dosing information and the UIRs just generated. It generates estimates for the fraction absorbed at 101 (default value) time points as specified in the Options tab, unless the Use Observed Times for Deconvolution checkbox is selected.
Note: Even if the UIR and (average) Fraction Absorbed are already known, all InVivo settings must still be specified in order to generate the correct output.
To skip UIR generation and deconvolution, select the Data already deconvolved and averaged option button in the “In Vivo Data Options” area.
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