Analysis of a three-period two-treatment pharmacokinetic study to assess scaled average bioequivalence

In the past years, various approaches for assessing bioequivalence of so-called 'highly variable drugs' have been debated. These are drugs whose pharmacokinetic profiles vary considerably when given to the same subject. As a consequence of the high variability, average bioequivalence between two such drugs can only be shown with an unfeasibly high number of subjects. Therefore, regulatory agencies generally agree that the criterion of average bioequivalence warrants adjustment for highly variable drugs. The mainstream of the most recent discussion favours an approach that is called scaled average bioequivalence. With this approach, the usual criterion of average bioequivalence is scaled by the within-subject standard deviation of the pharmacokinetic parameter in question. A parsimonious design for evaluating scaled average bioequivalence is a three-period two-treatment crossover trial where the reference drug is given twice and the investigational drug is given once to each subject. In this paper, it is shown how to analyse the data of such a trial with respect to the criterion of scaled average bioequivalence under the assumption of a log-normal distribution of the pharmacokinetic parameter. Explicit SAS® code for the analysis is provided.