Power bioequivalent studies

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... 

Subsequent studies in our laboratory have reproduced the above results and demonstrated that similar formulations will produce similar R S ratio vs. time profiles (plots C in Fig. 4), whereas dissimilar formulations produce R S ratio vs. time profiles that appear to differ in subtle but discernible ways (plots B in Fig. 4). Since differences in the 1 S ratio vs. time profiles were seen even as the formulations met the rigorous bioequivalency criteria for each of the four analytes, the R S ratio may be a powerful tool in helping to identify and understand the interaction between absorption rate and differential saturation of metabolic enzymes. 

Although the two-period crossover design has certain intrinsic weaknesses, intra-individual variation is usually smaller than variation between subjects, and bioequivalence can usually be established using a smaller number of subjects in a crossover study. The order in which subjects receive single doses of the different formulations must be randomised and an adequate interval allowed between doses to ensure washout. The number of subjects will depend on the variability of the kinetics of the compound. A power calculation should be performed using historical data, if possible. In practice, the minimum number of volunteers needed is 12 and the maximum usually about 24 but is occasionally more. The number and times of blood samples is a critical a sufficient number of samples is required around the to permit and to be identified with adequate accuracy. Sampling should continue for at least 3-4 half-lives and later samples should be spaced so that no more than about 15% (or ideally 10%) of the AUC has to be determined by extrapolation or interpolation between points. Model-fitted data are usually not acceptable should be obtained directly from the observed concentration data and... 

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