The analyte to be evaluated in bioequivalence trials is still today a controversial issue. The objective of this work is to use computer simulation approach to solve gaps in regulatory guidances regarding bioavailability (BA) and bioequivalence assessment (BE), especially in drugs undergoing metabolic clearance. Finally, the conclusions of the present work can lead to new recommendations for analyte selection in the BE trials.

Materials and methods: Simulated BE studies were performed using NONMEM. A semi-physiological model was used, including dissolution compartment, degradation in lumen, operative absorption time and hepatic first-pass effect. Parent drug and metabolite were simulated for both reference and test.

Inter-occasion and inter-individual variability was included for some of the parameter, and intra-individual variability for the plasma concentration of both parent drug and plasma concentration.

To simulate non-bioequivalent formulations, different scenarios were performed by varying the values of dissolution constant in lumen or the degradation in lumen or the operation absorption time or a combination of all three.

On top of that, the hepatic clearance and its inter-individual variability was also varied to detect any dependency in the best analyte to choose (parent drug or metabolite) and the hepatic clearance.

Results: The results of all the simulations will be presented as percentage of success for the metabolite and the parent drug. The scenarios will be split on 2 groups, either test and reference were truly bioequivalent or they did not.

Conclusions: Finally, either metabolite or parent drug would be selected depending on the results of the simulation.