Simultaneous confidence regions for multivariate bioequivalence

Demonstrating bioequivalence of several pharmacokinetic (PK) parameters, such as AUC and C-max, that are calculated from the same biological sample measurements is in fact a multivariate problem, even though this is neglected by most practitioners and regulatory bodies, who typically settle for separate univariate analyses. We believe, however, that a truly multivariate evaluation of all PK measures simultaneously is clearly more adequate. In this paper, we review methods to construct joint confidence regions around multivariate normal means and investigate their usefulness in simultaneous bioequivalence problems via simulation. Some of them work well for idealised scenarios but break down when faced with real-data challenges such as unknown variance and correlation among the PK parameters. We study the shapes of the confidence regions resulting from different methods, discuss how marginal simultaneous confidence intervals for the individual PK measures can be derived, and illustrate the application to data from a trial on ticlopidine hydrochloride. An R package is available.