Evaluation of area under the concentration curve adjusted by the terminal‐phase as a metric to reduce the impact of variability in bioequivalence testing

Abstract

To quantify the utility of a terminal-phase adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than the volume of distribution (V). Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits. When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test. The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.