Absorption IVIVC correlation

It is important to recognize that the in vitro permeability obtained in cell mono-layers (such as Caco-2 models) should be considered as a qualitative rather than quantitative value. Especially poor are predictions of fraction dose absorbed for carrier-mediated drugs with low Caco-2 permeability and predictions of high fraction dose absorbed in humans [7, 20, 42, 48, 51]. However, it is possible to establish a reasonably good IVIVC correlation when passive diffusion is the dominating absorption mechanism. 

The jejunal perfusion approach generates data which may be used to predict absorption/bioavailability and to establish in vivo-in vitro correlation (IVIVC) even for extended release (ER) products. If a dmg is transported mainly by passive diffusion and has a jejunal Peff higher than metoprolol (1.5 x 10-4 cm s 1 = high-permeability compound), it can be expected to be completely absorbed throughout the small and large intestine [5, 46]. 

In vitro dissolution testing is an important tool in the development of solid drug products, as well as in batch quality controls. The aim of the test is to see that the drug is appropriately dissolved in the gastrointestinal tract and made available for absorption. It is therefore highly desirable that the in vitro tests provide data that correlate to the in vivo situation. However, attainment of IVIVC has often failed-and the concept of IVIVC has been challenged. 

The simple reading of these definitions allows the distinction between two main types of correlations to be made. Level A correlations that use all the information of the dissolution and absorption curve (Table 1 and Fig. 1). For Level A, each regression line represents a set of information relation to one type or one formulation. For Levels B or C, the establishment of a relationship implies the use of many formulations, each of them giving one pair of data (vitro and vivo. Table 1, Fig. 2). The establishment of Level B and C needs more data and, as they do not use all the information related to vitro and vivo behavior of the formulation, they are less powerful. The FDA ranked the levels as follows A Level A IVIVC is considered to be the most informative and is recommended, if possible. Multiple Level C correlations can be as useful as Level A correlations. However, if a multiple Level C correlation is possible, then a Level A correlation is also likely and is preferred. Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected. Level B correlations are least... 

As denoted above, the rate-limiting step in the oral absorption of Class II drug substances is often the in vivo dissolution [23-25]. Hence, a well-designed dissolution test should be capable of providing adequate in vitro-in vivo correlation (IVIVC). 

As discussed above, the rate-limiting step in the oral absorption of Class II drug substances is likely to be the in vivo dissolution [23-25]. For Class II dissolution rate limited drugs, hence, if in vivo dissolution can be estimated in vitro, an in vitro-in vivo correlation may be established. As discussed in Section 3.5, such media have been developed, and an adequate IVIVC was shown for number of Class II drugs. However, due to the numerous in vivo parameters involved, it appears that more research is needed to develop uniform dissolution media reflecting in vivo dissolution conditions, to establish an adequate IVIVC, and to asses the risk of bioinequivalence [86, 88], In addition, the relationship between the hydrodynamics in the currently available dissolution tests and the actual in vivo situation is not adequately characterized and might interfere to obtain the correlation. 

The in vitro-in vivo correlation (IVIVC) is an extremely useful exercise at the preformulation level that determines how scale up and post approval changes or Biowaiver principles would be exploited. Conceptually, IVIVC describes a relationship between the in vitro dissolution/release versus the in vivo absorption. This relationship is an important item of research in the development of drug... 

Level A correlation This correlation represents a point-to-point relationship between in vitro dissolution and in vivo dissolution (input/absorption rate). Level A IVIVC is also viewed as a predictive model for the relationship between the entire in vitro release time course and entire in vivo response time course. In general, correlations are linear at this level. Although a concern of acceptable nonlinear correlation has been addressed, no formal guidance on the nonlinear IVIVC has been established. Level A correlation is the most informative and very useful from a regulatory perspective. 

Where dissolution or drug release is the rate-limiting step to drug absorption, it may be possible to establish an in vitro-in vivo correlation (IVIVC) whereby validated predictions of in vivo performance may be made from in vitro dissolution data. 

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