Bioequivalence and Residue Depletion Profiles

The assessment of bioequivalence is based on 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration. This method is equivalent to two one-sided tests with the null hypothesis of bio-inequivalence at the 5% significance level. Two products are declared bioequivalent if upper and lower limits of the confidence interval of the mean (median) of log-transformed AUC and Cmax each fall within the a priori bioequivalence intervals 0.80-1.25. It is then assumed that both rate (represented by Cmax) and extent (represented by AUC) of absorption are essentially similar. Cmax is less robust than AUC, as it is a single-point estimate. Moreover, Cmax is determined by the elimination as well as the absorption rate (Table 2.1). Because the variability (inter- and intra-animal) of Cmax is commonly greater than that of AUC, some authorities have allowed wider confidence intervals (e.g., 0.70-1.43) for log-transformed Cmax, provided this is specified and justified in the study protocol. 

In relation to residues in food-producing species, it is important to recognize that demonstration of average bioequivalence does not obviate the need for separate residue depletion studies for a generic product. There are several reasons why this is so  

It is ciear that, for a parenterai product administered intramuscuiariy or subcutaneousiy, depiction from the injection site may weii be sufficientiy simiiar to provide bioequivaience variabies that faii weii within the preset iimits, but are nevertheiess sufficientiy different to yieid significant, even quite iarge, differences in concentration at the injection site.  

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