Simulations of bioequivalence trials using physiological-pharmacokinetic in single dose and steady state scenarios. Which scenarios are refusable?
Fernandez-Teruel Carlos (1), Gonzalez-Alvarez Isabel (2), Navarro-Fontestad Carmen (2), Garcia-Arieta Alfredo (3), 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) Pharmacokinetics service. Spanish Agency for Medicines and Heath Care Products
Objectives: The aim of this work is to continue the studies about bioequivalence (BE). In last studies, simulations about drugs undergoing saturable and non saturable metabolic clearance were assessed. Now the purpose is to evaluate scenarios for drugs class I to IV based on BCS at single dose and in steady state (SS).
Methods: The studies were simulated using NONMEM. In the model, a semi-physiological model was developed, 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 until the steady state was reached. Afterward AUC and Cmax within a dose interval were calculated to assess the ratios between reference and test.
To simulate the test and reference formulations, different scenarios were performed by varying the values of dissolution constant in lumen, absorption rate, solubility of parent drug, saturation of hepatic metabolism or combinations of all. In these scenarios variability between subjects was not included, as the achievement was establishing the most sensitive variable (parent, parent SS, metabolite and metabolite SS) in each scenario using AUC and Cmax ratios.
Results: Results of all simulations will be presented as percentage of success for the metabolite and the parent drug, classifying the drugs in classes from I to IV.
Conclusions: This work illustrates the differences between single dose and steady state concerning the AUC and Cmax ratios, Showing the parent drug at single dose or in steady state depending on the case are the most sensible variables.