The IVIVC tool within Phoenix is a convenient and powerful tool to build an in vivo-in vitro correlation model using dissolution experiments and real in vivo profiles. This module can support your organization in formulation development and even in applying for biowaivers.
The tool has a flexible library of built-in models that can be modified to better fit more complicated, non-linear relationships as demonstrated in the attached AAPS poster presentation.
To briefly summarize, the problem was to develop an In Vitro-In Vivo Correlation (IVIVC) model for a compound whose release rate specific bioavailability would not initially seem to support an IVIVC.
The formulation under evaluation is a capsule containing four different types of delayed release beads. Each bead is are characterized by a mean dissolution time (MDT) and a time lag (Tlag) and each of the seven formulations under study is comprised of a different ratio of each bead type.
Mean plasma profiles for 4 formulations (10-20 subjects per formulation) were deconvolved using the PK parameters that would relate to the intravenous kinetics of the compound. The generated series of fraction absorbed (Fabs) profiles were then overlaid with the dissolution profiles. Reviewing this plot suggested that the slower formulations had greater bioavailability than the fastest release (CR01) and the slower the release -the greater the bioavailability.
This meant that a simple library model could not describe the data well. Since the Levy plot indicated two time scales, a bi-linear model was proposed where an initial lag (TL1) to be consistent with a stomach emptying effect together with a Tcut representing intestinal transit time switching between phases.
In this case reviewing the original exploratory plots together with the diagnostic plots an initial library model was refined to consider some physiological mechanisms e.g. first pass metabolism greatest in the small intestine, thereby creating an acceptable custom IVIVC model.
However, occasionally when running a custom model, you may find that IVIVC model the object freezes (you can tell when this has happened because the status bar fails to advance)
Should this happen
- CTRL+SHIFT+Escape to bring up Windows Task Manager
- Navigate to the Processes tab.
- Try ending the wnlpk32.exe process
- It should automatically restart and then complete without error
- Take it as a reminder to save your Phoenix project!
If you would like to learn more about the IVIVC tool, then consider one of our training courses.
To learn more about how our clients are using the IVIVC Toolkit to accelerate generic drug development, please read this case study.