IVIVC

BCS Class II Low-solubility, high-permeability drugs. The bioavailability of products containing these compounds is likely to be dissolution-rate limited. For this reason, a correlation between in vivo bioavailability and in vitro dissolution rate (IVIVC) may be observed. 

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]. 

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. 

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 BCS could be used as a framework for predictions when IVIVC could be expected for solid IR products, as summarized in Table 21.5. It is important to realize that the in vitro dissolution test only models the release and dissolution of the active drug substance from the formulation, and it is only when these processes are rate-limiting in the absorption process that IVIVC can be expected. In... 

Tab. 21.5. Expectations for in vitro-in vivo correlations (IVIVC) for immediate release (IR) products based on BCS.

I High solubility/High Peff No IVIVC until product dissolution becomes slower than gastric emptying... 

II Low solubility/High Peff IVIVC should be possible to establish provided that in vitro relevant dissolution test method are used and drug absorption is limited by dissolution rate rather than saturation solubility... 

Class II drugs, i.e., low-solubility/high-permeability compounds, are expected to have a dissolution-limited absorption. Thus, for these types of drugs an IVIVC... 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

The absorption of class III drugs is limited by their permeability over the intestinal wall. Thus, as this process is not at all modeled by the classical in vitro dissolution test, no IVIVC should be expected. When drug dissolution becomes slower than gastric emptying, a reduction in the extent of bioavailability will be found in slower dissolution rates as the time when the drug is available for permeation over the gut wall in the small intestine will then be reduced. Thus, the same type of relationship can be expected between bioavailability and in vitro dissolution, as shown in Fig. 21.12 for a class I drug. 

Two kinds of general relationships can be established between the in vitro dissolution and in vivo bioavailability (1) IVIVC and (2) In vivo-in vitro associations. In the former, one or more in vivo parameters are correlated with one or more in vitro-release parameters of the product. In case of in vivo-in vitro associations, in vivo and in vitro performance of different formulations is in agreement, but a correlation does not exist per se. Situations can also exist where no correlation or association is possible between the in vitro and in vivo data (30). Regardless of which case applies, the extent of the relationships between the parameters must be clearly understood to arrive at a meaningful interpretation of the results (31). The procedures for comparing profiles and establishing an IVIVC are explained in detail in USP 27, Chapter < 1088 > and also addressed in Chapter 10 of this book. In the best case, IVIVC implies predictability of both similarity in and differences between in vitro and in vivo data in a... 

For IR dosage forms of highly soluble drugs, it is likely to be difficult to produce batches with widely enough varying dissolution characteristics to be able to establish an IVIVC (see Chapter 10). This is because of the need to have side-batches whose dissolution and absorption rates vary by at least 10% (each side of) the batch of interest, typically the pivotal batch or the marketed product. 

In vitro-in vivo correlation (IVIVC) is a general term that refers to a relationship between a biological property produced by a dosage form and a physicochemical characteristic of the same dosage form (1). Establishment of an IVIVC could... 

Development of a robust IVIVC is possible when absorption is limited by lumenal dissolution, provided lumenal dissolution (or release) is adequately simulated in vitro. 

IVIVCs can be divided into non-quantitative and quantitative. In non-quantitative correlations the two variables are not related to each other via a mathematical relationship. A characteristic example is the rank-order correlation that was popular in the 1970s (10-15). In quantitative correlations the in vitro variable correlates with the in vivo variable via a linear or a non-linear equation. A quantitative IVIVC can be established, with or without the framework of a model, by using estimated values of characteristic parameters of the in vitro dissolution process and estimated values of the characteristic parameters of the in vivo arrival-in-bloodstream... 

However, single-point correlations are of limited value for two reasons. The first relates to the choice of the specific parameters to be correlated. Although there are some procedures in the literature that could be used for selecting the most appropriate parameter [e.g., the quadrant analysis (16,17)], these are not easy to apply in practice and the choice is usually based on a best-result basis. Another reason is that two processes having the same value of the chosen characteristic parameter can be different in terms of their overall shape. Consequently, a quantitative IVIVC is much more informative if established using all available in vitro and in vivo raw data these are termed multiple-point or point-to-point correlations. 

Point-to-point IVIVCs can be established by using two approaches. The first approach is to establish a relationship between the actual time course of the in vitro dissolution and the time course of the lumenal dissolution or arrival into the general circulation (Fig. 1), as estimated by deconvolution of the observed concentration in the bloodstream vs. time profile. The second approach is to establish a relationship... 

Figure 1 Schematic of the two approaches usually followed for developing a point-to-point IVIVC. Procedure 1 has two steps (a and b) and involves deconvolution of a concentration-in-blood-stream vs. time profile. Procedure 2 has also two steps (a and b) but involves convolution of a concentration-in-bloodstream vs. time profile.

At both the evaluation and the application level of a point-to-point IVIVC, in vitro dissolution data sets need to be treated and/or compared with each other. Appropriate methods vary with the data collection procedure and whether or not a model is to be fitted to the data. 

In IVIVC, it has become common practice to define methods as model dependent, if they take into account that data points... 

The right panel illustrates a correlation (sometimes termed Levy ) plot of the same data, which is widely used in IVIVC. Here, fractions FT(t) and FR(t), dissolved at the same time, are plotted against each other, which ease vertical comparison. An equally justifiable alternative would be to stress the horizontal aspect by plotting time values tT(F) and tR(F) for the same F value against each other. In both... 

Model-dependent comparison of two time profiles is best achieved in terms of the semi-invariants discussed earlier in the section on Characterization of Semi-invariants ( Moments ). This treatment is in accordance with the Level B definition of IVIVC, as proposed in several official guidelines. It makes full use of the underlying model that the data are presented by a distribution function, but no specific function is required. Although derived function parameters (e.g., Weibull, polyexponential, etc.) may be used, the computation may also be performed numerically on the observations as such. 

Within the scope of biopharmaceutics and IVIVC, bootstrap techniques have been applied to several specific problems related to the estimation of confidence intervals of, e.g., the similarity factor/ (21), the Chinchilli metric (27), parameters of an open two-compartment system (32), and the SD in general (33). From these few applications, it cannot be judged how much is actually gained from these new techniques. 

Langenbucher F. IVIVC indices for comparing release and response profiles. Drug Dev Ind Pharm 1999 25 1223-1225. 

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