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vivo systems behave linearly from a kinetic standpoint, both dissolution kinetics and pharmacokinetics. The intercept of such a correlation relates to the bioavailability while the slope relates to the dissolution rate. The correlation coefficients of such a comparison will be close to unity since the system response is computed as a back calculation from the observed fitting of data to a model. However the slope and the intercept of this correlation provide key information about the in vitro and in vivo performance of the formulation(s). Two products may be bioavailable but their rate and extent to which they dissolve both in vitro and in vivo may differ. In such cases, the intercept will be the same but the slope of such correlation will be different. In the six data sets shown in Fig. 32 two data sets clearly are superior, three sets are average, and one set is inferior. This pattern is reflected in the dissolution profiles, the plasma profiles, and the fractional system response profiles. Thus the correlation is successful in discriminating and separating out the formulations that are behaving differently in spite of their claims to be similar. |
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The utility of this approach is obvious in the development and assessment of bioequivalence, or the lack of, between products. Products having the same fractional response profile intercept would have the same bioavailability, whereas products having both slope and intercept the same would be bioequivalent. Simplistically, it means that the fractional system-response correlation profiles for the test formulation(s) and the reference formulation should be superimposable in order to unequivocally demonstrate bioequivalence. In practice, however, such superimposability may not be possible. In general, one might want to set guidelines for deeming a product as bioequivalent based on allowable deviation, at a prescribed confidence level, from the fractional system-response correlation profile obtained for the reference formulation. Such a permissible deviation at 95% confidence level is adequate and a test formulation falling within these limits can be deemed bioequivalent with the corresponding reference formulation. |
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