For a dissolution test to be valuable in linking the formulation with efficacy and performance characteristics, establishment
of IVIVC or IVIVR is crucial. The IVIVC or IVIVR dissolution method can then serve as a guide for the development of a meaningful
quality control method, which will occur in Phase III clinical development. Figure 1 summarizes the different approaches that
can be undertaken to establish either IVIVC or IVIVR. A basic relationship might be found between API properties and PK data
(see Figure 1, Level 1). This relationship can be in the form of a rank order or can be modeled mathematically (6) In the
second level, deconvolution of PK data might be used to establish IVIVC or IVIVR. The relationship can be achieved by correlating
the fraction of dose dissolved versus the fraction of dose absorbed, estimated by deconvolution. In most cases, however, this
correlation requires that the absorption process is dissolution controlled. For IR products, this approach mostly fails or,
in some cases, requires a scale factor between in vitro and in vivo data (7). For extended-release products, there is a high probability of establishing IVIVC. When IVIVC cannot be established
using deconvolution, convolution-based models should be used (see Figure 1, Level 3). Convolution-based approaches use models
such as the Advanced Compartmental Absorption and Transit (ACAT) model or other PK models to predict the oral performance
of a dosage form (8). In vitro data are used in these models to predict the plasma time curves. Such a prediction, if established by using the appropriate
parameters, is a Level A correlation (9).
Figure 1. (FIGURES ARE COURTESY OF THE AUTHORS.)
Determination of IVIVC and IVIVR is a continuous effort throughout development. It requires input of data, including human
PK levels and pharmacodynamic properties, food effects, API properties (BCS), and dosage-form information (i.e., excipient
properties). Computer tools such as "GastroPlus" (Simulations Plus, Lancaster, CA), "PDx-IVIVC" (GloboMax, Hanover, MD), and
"WinNonlin" (Pharsight, Mountain View, CA) can be used to develop IVIVC and IVIVR.
Figure 2 shows a flow chart detailing when IVIVR or IVIVC can be established and when it is unlikely that a differentiation
between formulations and their in vivo behavior can be found. A drug might be either dissolution or absorption controlled (10). Any formulation changes should be
assessed according to the drug's impact on either the dissolution or absorption properties. The impact on absorption, however,
is normally assessed in vivo and in vitro screening tools then must be developed to assess excipient effects on the absorption.
Figure 2. (FIGURES ARE COURTESY OF THE AUTHORS.)
If the dissolution of an API is slower than its absorption in the GI tract (this typically occurs for BCS II drugs), then
the API's behavior is similar to an extended-release dosage form. A critical study to consider in this case would be dissolution
testing with different drug-substance particle sizes. If the dissolution rate is controlled by particle size, IVIVC or IVIVR
may be attempted. If a drug dissolves quickly from the dosage form, however, as for most IR products and absorption is the
time-limiting factor, then IVIVC or IVIVR will not be possible using conventional deconvolution-based correlation between
dissolution data and PK parameters. In such cases, only convolution-based computer simulations should be attempted by predicting
the observed plasma levels.
A number of modeling programs are being used in drug-release studies (e.g., Simulations Plus' "DDDPlus" and "GastroPlus").
These programs may allow prediction of the effects of formulation changes on dissolution and absorption behavior. Such models
can predict how absorption might be affected by factors such as API particle size and may result in the development of a more
relevant dissolution method.