Simulations of bioequivalence trials using physiological-pharmacokinetic models with saturable and non-saturable hepatic clearance
Fernandez-Teruel Carlos (1), Gonzalez-Alvarez Isabel (2), Navarro-Fontestad Carmen (2), Nalda-Molina Ricardo (3), Garcia-Arieta Alfredo (4), Bermejo-Sanz Marival (2), Casabo-Alos Vicente (2).
(1) Intervalence Biokinetics, Spain. (2) Department of Pharmacy and Pharmaceutics, Faculty of Pharmacy, University of Valencia, Spain. (3) Pharmacy and Pharmaceutics Division, Faculty of Pharmacy, Miguel HernŠndez University, Spain. (4) Pharmacokinetics service. Spanish Agency for Medicines and Health Care Products
Objectives: 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 a saturable metabolic clearance. Finally, the conclusions of the present work can lead to new recommendations for analyte selection in the BE trials..
Methods: Simulated BE studies were performed using NONMEM. A semi-physiological model was used, including dissolution compartment, operative absorption time and hepatic first-pass effect with saturable and non-saturable metabolism. Parent drug and metabolite were simulated for both reference and test.
Inter-occasion and inter-individual variability were 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, the absorption rate, the saturation of hepatic metabolism or combinations of all.
On top of that, the hepatic clearance and its inter-individual variability were also varied to detect any dependency in the selection of the best analyte (parent drug or metabolite).
Results: Results of all simulations will be presented as percentage of success for the metabolite and the parent drug. The scenarios will be split into 2 groups for establishing the truly bioequivalence between reference and test.
Conclusions: Finally, either metabolite or parent drug would be selected depending on the results of the simulation.