Aim: 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).
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: between occasion variability; bioequivalence; clearance; crossover; terminal-phase adjusted area under the concentration curve.
© 2021 British Pharmacological Society.