european journal of pharmaceutical sciences 36 ( 2 0 0 9 ) 137–146 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ejps Computer simulations of bioequivalence trials: Selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Linear kinetics (I) Carlos Fernández-Teruel a,1 , Ricardo Nalda Molina a,1 , Isabel González-Alvarez b,1 , Carmen Navarro-Fontestad a,1 , Alfredo García-Arieta c,2 , Vicente G. Casabó a , Marival Bermejo b,* a Departmento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Valencia, Vicent Andres Estelles s/n, 46100 Burjassot Valencia, Spain b Departamento de Ingeniería, Area Farmacia y Tecnología, Facultad de Farmacia, Ctra. Alicante-Valencia, Km 87, 03550 Sant Joan d’Alacant, Alicante, Spain c Pharmacokinetics Service, Division of Pharmacology and Clinical Evaluation, Human Use Medicines, Spanish Agency for Medicines and Health Care Products (AEMPS), Campezo 1, Madrid E-28022 Spain article info Article history: Received 4 July 2008 Accepted 8 September 2008 Published on line 5 November 2008 Keywords: Bioequivalence First-pass metabolism Linear Single dose Steady state BCS abstract Modeling and simulation approaches are useful tools to assess the potential outcome of different scenarios in bioequivalence studies. The aim of this study is to propose a new and improved semi-physiological model for bioequivalence trial simulations and apply it for all BCS (Biopharmaceutic Classification System) drug classes with non-saturated first- pass hepatic metabolism. The semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Parent drug and metabolite levels for both reference and test were simulated. Eight types of drugs (with high or low permeability and high or low solu- bility (class I to IV) and high or low intrinsic clearance) were considered in two variability scenarios (high-low) and in six test products of decreasing biopharmaceutic quality. The scenarios were tested in single dose and steady state studies. In case of drugs with non- saturated hepatic first-pass effect (and no gut-wall metabolism) the parent drug is usually the most sensitive analyte and the single dose design is usually the most sensitive study design to detect the worsening of the biopharmaceutic quality of the test formulation. The only exception to this general conclusion was observed in class III drugs (high solubility, low permeability) with low intrinsic clearance for which the parent drug C max ratio in steady state shows higher sensitivity followed by the metabolite C max ratio in single dose. This excep- tional behaviour is caused by a limited operative absorption time (or absorption window) in class III drugs that precludes complete absorption and produces a non-linear absorp- tion. Therefore, it can be concluded that the metabolite does not need to be measured if the drug has no gut-wall metabolism and shows linear pharmacokinetics. Interestingly, ∗ Corresponding author at: Facultad de Farmacia, Ctra. Alicante-Valencia, Km 87, 03550 Sant Joan d’Alacant, Alicante, Spain. Tel.: +34 96 3544916; fax: +34 963544911. E-mail address: mbermejo@umh.es (M. Bermejo). 1 These authors contributed equally to this work. 2 This article reflects the author’s personal opinion and not necessarily the policy or recommendations of the AEMPS. 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.10.014