Bioequivalence Trials Simulation to Select the Best Analyte for Drugs with Presystemic Intestinal and Hepatic Metabolism.
Navarro-Fontestad C. (1), Fernandez-Teruel C. (2), Gonzalez-Alvarez . (3), Garcia-Arieta A. (4), Bermejo M. (3), Casabo VG. (1).
(1) Department of Pharmacy and Pharmaceutics, Faculty of Pharmacy, University of Valencia, Spain. (2) Department of Clinical Pharmacology. Pharma Mar. (3) Department of Engineering, Faculty of Pharmacy, Miguel Hernandez University (4) Pharmacokinetics service. Spanish Agency for Medicines and Heath Care Products
Objectives: The aim of this work is to evaluate the chemical substance (parent drug or metabolite) more suitable for BE analysis. The semi-physiological model includes pre-systemic intestinal metabolism with efflux transporter from enterocyte to lumen in addition to the previous model (1, 2). Simulations about class I drugs undergoing saturable and non saturable metabolic clearance were performed.
Methods: The studies were simulated using NONMEM VI. A semi-physiological model was developed, including dissolution compartment, operative absorption time, efflux transport in gut, pre-systemic metabolism in gut and liver in addition to systemic metabolism. Four scenarios were simulated by combining high and low intrinsic clearance in liver or gut, and were evaluated at saturable and non-saturable conditions. Parent drug and metabolite plasma profiles were simulated for both, reference and test. Afterward AUC and Cmax 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 in vivo dissolution rate constant in lumen.
Results: Results of all simulations will be presented as percentage of BE success for the metabolite and the parent drug. In absence of efflux transport and non-saturable conditions, there are small differences between parent drug and metabolite in AUC and Cmax ratios, but when the metabolism becomes saturable, metabolite AUC and Cmax ratios are higher than 0.8 even when dissolution constant of test formulation is 12% of reference formulation, whereas parent drug is affected by formulation quality.
Conclusions: This work shows the differences between high and low intestinal or hepatic metabolism concerning the AUC and Cmax ratios, demonstrating that the parent drug is the most sensible moiety in most scenarios.
References:
[1]. C. Fernandez-Teruel, R. Nalda Molina, I. Gonzalez-Alvarez, C. Navarro-Fontestad, A. Garcia-Arieta, V.G. Casabo, and M. Bermejo. Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: linear kinetics (I). Eur J Pharm Sci. 36:137-146 (2009).
[2]. C. Fernandez-Teruel, I. Gonzalez-Alvarez, C. Navarro-Fontestad, A. Garcia-Arieta, M. Bermejo, and V.G. Casabo. Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Part II. Non-linear kinetics. Eur J Pharm Sci. 36:147-156 (2009).
Acknowledgments: This work is supported in part by Biosim EU grant : LSHB-CT-2004-005137 and Consolider-Ingenio 2010: CSD00C-07-25506
