జర్నల్ ఆఫ్ బయోక్వివలెన్స్ & బయోఎవైలబిలిటీ

నైరూప్య

Models, Optimal Sampling and Bioequivalence-A New Paradigm Case Study for a Drug with Complex Absorption Modified Release Methylphenidate

Andre J. Jackson*, Mutaz Jaber, Henry C. Foehl, Inder Chaudhary

Purpose: The purpose of the investigation was to compare the performance of ordinary sampling versus optimal sampling in Bioequivalence (BE) studies for an Extended-Release (ER) oral Methylphenidate (MP) tablet with complex absorption Concerta^®.

Methods: For approval of generic versions of Concerta^®, the FDA recommends a replicated crossover BE study design be used to define subject-by-formulation interaction variance and inclusion of pAUC (partial Area-Underthe-Curve metrics), in addition to standard metrics. Comparisons between ordinary and optimal sampling for the metrics was determined by the calculation of 90% Confidence Intervals (CIs) for selected Test/Reference (T/R) ratios (0.8, 0.9,0.95,1.0,1.10, and 1.25) for K0fast (zero-order fast absorption rate constant) and KAslow (first-order slow absorption rate constant). The effects of varying the values for FA (Fraction Absorbed) T/R ratios were also studied. Simulations were done using the recommended BE study methods above using a literature-sourced MP model. In addition, optimal sampling was measured against ordinary sampling obtained from a generic MP drug product vs. Concerta® in a human volunteers BE study.

Results: The ordinary and optimal sampling schemes resulted in comparable performance of the 90% CIs for the BE metrics pAUC: 03 hrs, pAUC: 37 hrs, pAUC: 712 hrs, and the standard metrics C_max, AUC_0-t for the simulations and the experimental MP data.

Conclusion: These results indicate that optimal sampling and ordinary sampling give essentially the same BE results for a MP ER drug product with complex absorption.