Level A IVIVC Required Inputs and Established Steps

To carry out a Level A IVIVC for a drug candidate, the following inputs are required:

• The in vitro dissolution data from formulation batches that have been tested in vivo.

• The in vivo C_p-time profiles for the reference formulations, where the reference formulations are either IV, solution, or immediate release doses that are used for building and calibrating the required PK model.

• The in vivo C_p-time profiles after controlled release dosing.

The established scientific steps for carrying out Level A IVIVC are as follows:

1. Deconvolution - Use a traditional or mechanistic deconvolution method to determine the in vivo input rate, where the in vivo release profile can be described by a single, double, or triple Weibull function. See Level A IVIVC Deconvolution.

2. Correlation - Establish a point-to-point correlation between the in vitro dissolution and the in vivo input rate, which is either bioavailability or dissolution versus time.

• You can model this correlation as either a linear correlation model, a power function model, a 2nd order polynomial model, or a 3rd order polynomial model.

• If you use a mechanistic deconvolution method, then a shifting and scaling function is also available.

3. Validate the IVIVC.

4. Convolution - Use the IVIVC and in vitro dissolution curve to predict the C_p-time profile for the candidate drug.