Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool
Andrés Figueroa-Campos,
Bárbara Sánchez-Dengra,
Virginia Merino,
Arik Dahan,
Isabel González-Álvarez,
Alfredo García-Arieta,
Marta González-Álvarez,
Marival Bermejo
Affiliations
Andrés Figueroa-Campos
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Juan de Alicante, Spain
Bárbara Sánchez-Dengra
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Juan de Alicante, Spain
Virginia Merino
Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, 46100 Valencia, Spain
Arik Dahan
Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
Isabel González-Álvarez
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Juan de Alicante, Spain
Alfredo García-Arieta
Service of Pharmacokinetics and Generic Medicines, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products, 28022 Madrid, Spain
Marta González-Álvarez
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Juan de Alicante, Spain
Marival Bermejo
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Juan de Alicante, Spain
The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f2 similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.
