What is IVIVCPlus™?
The IVIVCPlus Module is an optionally-licensed add-on module that extends the capabilities of GastroPlus by providing a convenient way to develop a standard level A in vitro-in vivo correlation or utilize the mechanistic approach to
determine the relationship between the dissolution of tablets and capsules in a laboratory and the dissolution in the gastrointestinal tract of humans and animals.
In the past, the failure to understand this important correlation has cost the pharmaceutical industry many millions of dollars and years of delay, as formulations under development were changed without specific direction and human trials had to be repeated. This module is expected to be of special interest to pharmaceutical companies designing time-release formulations for both new and existing drugs. The number of compounds anticipated in time-release formulations is expected to increase, as these formulations can allow a pharmaceutical company to obtain a new patent for a drug product losing exclusivity. In addition, having an IVIVC provides valuable guidance for a pharmaceutical company wishing to explore product life extension opportunities to obtain additional therapeutic claims or to reduce dosing frequency. Also, as outsourcing activities increase, IVIVCs can enable pharmaceutical companies to take full advantage of utilizing in vitro testing over expensive BE studies when undertaking scale-up and post approval changes.
IVIVCPlus provides a simplified, user-friendly and intuitive interface that is fully integrated with the main GastroPlus program. You can easily navigate between selection of methods and data sets to be used for deconvolution/correlation to find the most informative IVIVC as well as change the selection of data sets to be used in convolution to quickly evaluate the internal and external predictability of the IVIVC or predict Cp-time profile for new formulations.
With IVIVCPlus you can:
Run Deconvolution
:
Within the context of IVIVCPlus, deconvolution refers to calculating a compound’s in vivo release rate or absolute bioavailability rate from the oral plasma concentration-time profile.IVIVCPlus offers five methods for deconvolution:
1) Mechanistic Absorption Model (GastroPlus)
2) Numerical deconvolution
3) Wagner-Nelson (1-compartment model) – includes calculator of elimination rate constant from the terminal phase of Cp-time data
4) Loo-Riegelman (2-compartment model)
5) Loo-Riegelman (3-compartment model)
The Mechanistic Absorption Model (GastroPlus) directly deconvolutes the in vivo release rate. This allows correlations to be made between in vitro release and in vivo release. Levy plots can be generated (time of in vitro vs. time of equivalent in vivo release). The Mechanistic Absorption Model deconvolution method expands IVIVCPlus, to include PBPK-based models, or saturable clearance if the compound exhibits nonlinear pharmacokinetics. It can also take into account intestinal first pass metabolism, pH-dependent solubility, and site-dependent absorption for compounds whose uptake is affected by intestinal transporters, changes in tight junction gap, or ionization.
The other four methods are traditional deconvolution methods that calculate the rate of appearance of compound in the systemic circulation.The absolute bioavailability rate is defined as the rate of appearance of compound in the systemic circulation divided by the dose.
Fit Correlation
:
Depending on the deconvolution method selected, a correlation can be made between in vitro release and in vivo release or absolute bioavailability and in vitro release. Currently, linear, power, and polynomial (first, second, or third order) functions may be selected for the functional form of the correlation.Only Level A Correlations are possible at this time in GastroPlus.
Save Deconvolution/Correlation Results
:
After finishing the deconvolution/correlation run, you have the option of saving the results for later use in predicting Cp-time profiles for new formulations or for running external validations on the fitted IVIVC.
Run Convolution
:
A fitted correlation function can be used to calculate an in vivo release-time profile or absolute bioavailability-time profile for a new formulation of the compound exhibiting a different in vitro release-time profile. A plasma concentration-time profile for the new formulation can be constructed with the calculated in vivo release-time or absolute bioavailability-time profile.
IVIVCPlus output includes:
• Correlation function statistics
• Statistics for match between experimental and convoluted Cp-time profile
• FDA required validation statistics (
observed values, predicted values, prediction errors, and mean absolute percent prediction error for both Cmax and AUC.These statistics can be used to evaluate the internal or external predictability of the correlation as described in the FDA’s Guidance for Industry Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations
)
• A number of plotting options after deconvolution, correlation, and convolution
• You can fully format the graph windows; plotted data and/or a graph image can be copied and pasted into another application, e.g., Microsoft Word, Microsoft PowerPoint, Microsoft Excel, etc...
For further information about licensing IVIVCPlus, please contact:
Mr. John DiBella
Director, Marketing & Sales
661-723-7723 ext. 244
john.dibella@simulations-plus.com