Multiple testing for bioequivalence with pharmacokinetic data in 2 x 2 crossover designs.

To evaluate globally the average bioequivalence of a test drug to a reference drug in a pharmacokinetic (PK) study under a 2 x 2 crossover design, we consider directly comparing the associated drug concentration-time curves. Statistical models for the drug concentrations are suggested when the concentrations measured at different time points are distributed according to a generalized gamma distribution and the mean concentrations over time is described by a one-compartment PK model. A multiple test based on the supreme distance between the two curves over the time interval under study is then proposed for testing the equivalence of the two drug concentration-time curves. The results of a Monte Carlo study suggest that, comparative to the conventional univariate and bivariate tests, the proposed test is more powerful for detecting the global bioequivalence and superior on maintaining its level when the global bioequivalence is violated. The application of the proposed tests is finally illustrated by using the data in a PK study involving two brands of benzbromarone tablets for reducing the uric acid.