Bioavailability testing 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. 

Internal predictability is established for each formulation used to develop the IVIVC model. Based on in vitro data, the IVIVC relationship is used to recalculate the initial in vivo curves, and then the predicted bioavailability is compared to the observed bioavailability for each formulation and a determination of the error prediction is made. Internal predictability is acceptable when the average percent prediction error is below 10% for Cmax and AUC, and none of the formulations have a prediction error greater than 15%. If the results are not acceptable, then external formulation with new test data are needed corresponding to an external predictability process. 

The plasma concentration-time data of a test formulation can be predicted from a dissolution-time profile, obtained from the in vitro model, and measured plasma concentrations for a reference formulation in the IVIVC bioavailability study (e.g., an oral solution), by use of convolution (see previous section). The difference in Cmax and AUC based on predicted and measured plasma concentrations can be numerically assessed for each formulation by a simple estimation of the relative difference, denoted prediction error (PE), as follows ... 

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