pharmaceutics Article An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products Isabel Gonzalez-Alvarez 1,2 , Marival Bermejo 1,2, * , Yasuhiro Tsume 1 , Alejandro Ruiz-Picazo 2 , Marta Gonzalez-Alvarez 2 , Bart Hens 1 , Alfredo Garcia-Arieta 3,† , Greg E. Amidon 1 and Gordon L. Amidon 1   Citation: Gonzalez-Alvarez, I.; Bermejo, M.; Tsume, Y.; Ruiz-Picazo, A.; Gonzalez-Alvarez, M.; Hens, B.; Garcia-Arieta, A.; Amidon, G.E.; Amidon, G.L. An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products. Pharmaceutics 2021, 13, 507. https://doi.org/10.3390/ pharmaceutics13040507 Academic Editor: Werner Weitschies Received: 2 March 2021 Accepted: 30 March 2021 Published: 7 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; isabel.gonzalez@umh.es (I.G.-A.); yasuhiro.tsume@merck.com (Y.T.); Bart.Hens@pfizer.com (B.H.); geamidon@umich.edu (G.E.A.); glamidon@med.umich.edu (G.L.A.) 2 Department Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain; alejandro.ruizp@umh.es (A.R.-P.); marta.gonzalez@umh.es (M.G.-A.) 3 División de Farmacología y Evaluación Clínica, Departamento de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, 28022 Madrid, Spain; agarciaa@aemps.es * Correspondence: mbermejo@umh.es; Tel.: +34-965-919217 † This manuscript represents the personal opinion of the author and does not necessarily represent the views or policy of the Spanish Agency for Medicines and Health Care Products. Abstract: The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia ® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental disso- lution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior. Keywords: gastrointestinal simulator; in vitro dissolution; BCS class II; weak base; dissolution modelling 1. Introduction After patent and/or exclusivity period expiry, generic products must demonstrate bioequivalence (BE) with the innovator product. Any further change on innovator or generic product needs the evaluation of the impact of those changes on product perfor- mance. In general, in vivo human BE studies are prescribed in regulatory guidelines unless a biowaiver approach (i.e., BE demonstration by applying an in vitro dissolution test) is claimed. This later situation is feasible for Biopharmaceutics Classification System (BCS) class 1 and 3 drug compounds or for BCS class 2 compounds with a validated level A in vitro in vivo correlation (IVIVC) [1,2]. In vivo predictive dissolution (iPD) methodolo- gies have been widely recommended for achieving a IVIVC for these compounds that may be extremely influenced by the surrounding variables of the gastrointestinal (GI) tract [3–5]. Pharmaceutics 2021, 13, 507. https://doi.org/10.3390/pharmaceutics13040507 https://www.mdpi.com/journal/pharmaceutics