A More Powerful Method to Analyze Bioequivalence for Endogenous Substances in a Crossover Design

• Activity Number: 505
• Type: Contributed
• Date/Time: Wednesday, August 12, 2015 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Li Fan* and Lata Maganti and Lori A. Mixson and Devan Mehrotra
• Companies: Merck and Merck and Merck and Merck
• Keywords: Bioequivalence ; Baseline ; Crossover ; Endogenous substances

Abstract

For most endogenous substances, bioavailability (BA) or bioequivalence (BE) is focused on the net increase in post dose exposures above their baseline levels in a crossover study design. With most endogenous substances (e.g. potassium, folic acid, thyroxin etc.), however, this could be small increase associated with large variability. Since the baseline concentrations of these substances are regulated by homeostatic equilibria, the FDA 2014 draft guidance proposed subtraction of the time-averaged baseline or time-matched baseline from the post-dose concentrations for evaluating BA/BE. We propose a new more powerful and efficient method for a crossover study to handle the baseline adjustments via the use of baseline differences as a covariate in our model. We support our new proposed method using simulations.