Convolution-based approaches for in vivo-in vitro correlation modeling.

One approach to in vivo-in vitro correlation (IVIVC) for extended release (ER) oral dosage forms is to directly model the relationship between the time courses of in vitro release and plasma drug concentrations. For drugs that exhibit linear, time-invariant disposition this can be done using models based on the convolution integral. Advantages of this approach relative to deconvolution-based IVIVC approaches include the following: The relationship between measured quantities (in vitro release and plasma drug concentrations) is modeled directly in a single stage rather than via an indirect two stage approach. The model directly predicts the plasma concentration time course. As a result: The modeling focuses on the ability to predict measured quantities (not indirectly calculated quantities such as the cumulative amount absorbed). The results are more readily interpreted in terms of the effect of in vitro release on conventional bioequivalence metrics. It is easier to construct methods that do not require the administration of an IV, oral solution, or IR reference dose. A variety of convolution-based IVIVC models and modeling strategies are possible depending on the relationship between in vivo and in vitro release, the existence of nonlinear absorption or presystemic biotransformation, and the in vivo study design. The simplest approach is applicable to the case where the in vitro release rate equals the in vivo release (or absorption) rate and the study design includes the administration of an IV, oral solution, or IR dose. That basic convolution-based method can be extended to adjust for differences between the in vitro and in vivo release rates. This is accomplished by formally modeling those differences. Potential models include time-scaling and convolution. The extent of drug absorption may sometimes depend upon the release rate. This may be due to phenomena such as saturable presystemic biotransformation or truncated absorption due to intestinal transit past the sites of absorption. The relationship between the in vitro release rate and extent of absorption may be modeled empirically or mechanistically. Such models may be coupled with convolution to construct an overall IVIVC model for the relationship between in vitro release and plasma drug concentrations. It is also possible to apply convolution-based IVIVC models to study designs in which no IV, oral solution, or IR dose has been administered. Details of the various modeling approaches listed above are presented. Selected approaches are illustrated by examples of their application to real data.