Validation of Sample Size Estimation by Bootstrapping Technique: Reference-scaled Average Bioequivalence Study

A new technique was used and validated to estimate pivotal sample size from pilot study data and to establish Bioequivalence (BE) of Highly Variable Drugs (HVD), paroxetine, in human subjects under fed conditions using ghatti Gum as a rate controlling membrane, by reference scale design.

Bootstrapping technique was adopted to calculate the pivotal sample size from pilot study data for HVD paroxetine. The reliability and validation of the method were tested in a semi replicate three sequence (RRT, RTR, and TRR where T stand for test drug and R stand for reference drug) cross-over BE study in 24 healthy subjects under fed conditions. Extended-Release (ER) matrix tablets were prepared by wet granulation technique

The ratio of the Pharmacokinetic (PK) metric obtained from the bootstrapping technique after log transformation was 1.04 for Cmax, 1.23 for AUCT, and 1.21 for AUCI with corresponding power of the study which was greater than 80% from pilot study data simulation. The ratio of the PK metric obtained from the reference scaling design in the present study was 1.00 for Cmax, 1.21 for AUCT, and 1.17 for AUCI. The upper limit of the Cmax, AUCT, and AUCI at 95% confidence limit was -0.143, -0.136, and -0.17, respectively.

Reference scaling approaches were used to establish BE and test product found BE with respect to the reference formulation, and hence, we can conclude that the ghatti gum can be used as rate-controlled membrane in certain concentration to develop CR formulation of other drugs.