Bioequivalence trials simulation to select the best analyte for drugs with two metabolic pathways
C. Navarro(1), C. Fernandez-Teruel(2), I. Gonzalez-Alvarez(3), A. Garcia-Arieta(4), M. Bermejo(3), VG Casabˇ(1)
(1)Faculty of Pharmacy, University of Valencia. (2)Department of Clinical Pharmacology. Pharma Mar. (3)Faculty of Pharmacy, Miguel Hernandez University. (4)Pharmacokinetics service. Spanish Agency for Medicines and Heath Care Products
Objective: To evaluate the chemical substance (parent drug or metabolite) more suitable for BE analysis.
Method: A semi-physiological model was used including two metabolic pathways in pre-systemic intestinal and hepatic metabolism, in addition to the previous model [1, 2]. Simulations about four BCS drugs undergoing saturable and non saturable metabolism were performed. The studies were simulated using NONMEM VI.
Results: Results are presented as percentage of BE success. In non-saturable conditions, there are small differences between parent drug and metabolites in AUC and Cmax ratios.When the metabolism becomes saturable, the principal and secondary metabolites AUC and Cmax ratios are larger than parent drug ratios. However, when only the principal metabolic route is non-linear, although parent drug is more sensitive than both metabolites, as the dissolution constant rate decreases, the principal metabolite AUC increases and it reaches values higher than the reference one.
Conclusion: Evaluating drugs with two pre-systemic metabolic routes, the metabolites do not show higher sensitivity than the parent drug to detect changes in the pharmaceutical performance, even when pharmacokinetics of the parent drug is non-linear.
. C. Fernandez-Teruel et al. 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).
. C. Fernandez-Teruel et al. 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 part of project SAF-2009-12768 funded by Spanish Ministry of Science and Innovation.