Replicated Crossover Designs in Bioavailability and Bioequivalence Trials *

Abstract

The concept of bioequivalence is illustrated in terms of prescribability for population bioequivalence and switchability for individual bioequivalence. Population bioequivalence or prescribability examines closeness of the distributions of the pharmacokinetic responses between the test and reference formulations obtained from a group of the same subjects. Individual bioequivalence or switchability is the interchangeability between the test and reference formulations within the same subject. It, then, requires equivalence between the two marginal distributions of the pharmacokinetic responses from the same subject. Replicated crossover designs, for each subject, can provide the estimates not only of the individual formulation effects but also of the individual intrasubject variabilities. Hence, for each subject, the marginal distributions of the test and reference formulations can be examined. Statistical methods are illustrated to examine the homogeneity of individual formulation effects and individual intrasubject variabilities. Under the assumptions of homogeneous individual formulation effects and individual intrasubject variabilities, summarized statistical measures and statistical test procedures are derived for assessment of both population and individual bioequivalence. A numerical example illustrates the proposed statistical methods.