Bioequivalence and Bioavailability Forum

Hi olacy
I suggest to perform a four way cross-over study with the following treatments:

Treatment A): 1 x 80 mg test
Treatment B): 1 x 80 mg reference
Treatment C): 2 x 40 mg test
Treatment D): 1 x 40 mg test

You need to demonstrate bioequivalence between Treatment A) and B) and between Treatment C) and B). Treatment D) should be added to assess if the pharmacokinetics are linear in the range of 40-80 mg dose. Assessment of linearity should consider whether differences in dose-adjusted AUC meet a criterion of ± 25%.

If the evaluation of treatment D) demonstrates linearity everything is fine, if the evaluation of treatment D) demonstrates, that the drug shows non-linear pharmacokinetics characterised by a more than proportional increase in AUC, you are on the safe side since the bioequivalence study should in general be conducted at the highest strength. If the evaluation of treatment D) demonstrates a less than proportional increase in AUC you have a problem since bioequivalence should in such cases be established both at the highest strength and at the lowest strength. In this situation you should argue with the authority that a study with half tablet of the 80 mg reference formulation is not feasible.
I hope this helps
Kind regards
Dan