The Value of In Vitro Dissolution in Drug Development - Pharmaceutical Technology

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The Value of In Vitro Dissolution in Drug Development
A Position Paper from the AAPS In Vitro Release and Dissolution Focus Group

Pharmaceutical Technology
Volume 33, Issue 4, pp. 52-64

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).

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.

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.


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