IVIVC importance

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... 

A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled 7n vitro/In vivo Testing and Correlation for Oral Controlled/Modified Release Dosage Forms (1990) concluded that, while the science and technology may not always permit meaningful IVIVC, the development of an IVIVC was an important objective on a product-by-product basis. Procedures for development, evaluation, and application of an IVIVC were described. Validation of dissolution specifications by a bioequivalence study involving two batches of product with dissolution profiles at the upper and lower dissolution specifications was suggested. 

An important concept is that the less data available for inihal IVIVC development and evaluation of predictability, the more additional data may be needed to define completely the IVIVC s predictability. Some combination of three or more formulations with different release rates is considered optimal. 

Non-Narrow Therapeutic Index Drugs. If an IVIVC model is to be used in estimating the in vivo performance of formulations of non-narrow therapeutic index drugs, testing the model s predictability with a data set that differs from those data sets used to define the correlation may be desirable, but is not considered as important as for a narrow therapeutic index drug. 

Sunkara, G. andChilukuri, D., IVIVC an important tool in the development of drug delivery systems, Drug. Del. Tech., 3, 52, 2003. 

External predictability (Fig. 10) is extremely important and demonstrates the real predictive power of the IVIVC. This prediction is important when using an IVIVC as a surrogate for bioequivalence studies. External predictability is really a validation in the mathematical sense. This involves a new formulation with known in vivo performances that have not been used to develop the IVIVC. The IVIVC will be used based on the in vitro dissolution profile of this new formulation to predict the in vivo performances. The external predictability will be accepted if with a new formulation average percent prediction error is lower than 10% for Cmax and AUC. In the case of the average percentage prediction error being between 10 and 20%, results will be considered as inconclusive and additional sets of data will be needed. If average... 

The choice of medium is expected to play a very important role in the dissolution of BCS Class II drug substances. The media used need to closely represent the in vivo conditions in the upper GI tract to achieve a meaningful IVIVC. As discussed in this... 

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... 

In almost all studies, a reference formulation is needed, either as a comparator for assessment of relative performance compared to the test formulation, or as a simple vehicle, to characterise the drug substance pharmacokinetics. If the aim is to investigate the influence of certain formulations on the rate and extent of absorption, which is the case in early development or IVIVC studies, an oral solution of the drug is the first choice as a reference formulation. Stability of the solution, regarding drug compound degradation and precipitation, is an important factor to verify before study start. Inclusion of a parenteral reference formulation, if feasible, provides additional information, as will be further discussed below. 

It is important to realise that an established IVIVC is not a general characteristic of a drug compound that can freely be applied to all kinds of oral formulations. An IVIVC is, rather, specific for a certain type of formulation. The main limitation of IVIVCs is the problem of defining how large the changes made to a specific formulation can be without affecting the applicability of an established correlation. 

Despite the improved solubility behavior of loaded drugs observed in vitro, it is not obvious to gain an improved bioavailability also in vivo. There are also other obstacles to overcome before a drug reaches the systemic circulation than solubility issues, such as permeation across a gut wall and first-pass metabolism. In 2010, Wang et al. reported important results about in vitro-in vivo correlation (IVIVC) (Wang et al. 2010a). They observed that all the pharmacokinetic parameters of... 

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