I Gonzalez-Garcia (1, 3), V Mangas-Sanjuan (2), M Merino-Sanjuán (3), C Alvarez-Alvarez (4), J Diaz-Garzon (4), A Rodriguez-Bonnin (4), JJ Torrado-Duran (4), A GarcÃa-Arieta (5), IF Troconiz (1), M Bermejo (2)
(1) Pharmacometrics and Systems Pharmacology. Pharmacy and Pharmaceutical Technology Department. University of Navarra; (2) Pharmacy and Pharmaceutical Technology Area. Miguel Hernandez University; (3) Pharmacy and Pharmaceutical Technology Department. University of Valencia; (4) Department of Pharmacy and Pharmaceutical Technology, Complutense University of Madrid; (5) Head of Service on Pharmacokinetics and Generics, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products.
Introduction: In vitro-in vivo correlations (IVIVC) are defined, almost identically, by Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. IVIVC can be useful in product development for quantifying the in vitro release, evaluating formulation related effects on absorption, supporting in quality control for certain scale-up and post approval changes, and as a tool for setting in vitro dissolution specifications.
Objectives: The purpose of this work is to establish standard dissolution specifications based on a novel approach to ensure in vivo bioequivalence for a drug using simulated data.
Methods: A level A IVIVC was developed using differential equations. A one compartment model was assumed for drug disposition. Absorption and elimination were defined as first order processes.The internal validation of the IVIVC was performed using a VPC (n=1000) Then, new formulations were tested using stochastic simulations in order to establish the dissolution specification limits based on the 90% confidence interval of the p50 of the Cmax and AUC. Simulated data were fitted using non-linear mixed-effects modelling implemented in NONMEM 7.2. Simulations were performed using PsN and the R software.
Results: Differential equations method was successfully applied to establish a level A IVIVC and internal was achieved according to FDA and EMA limits. AUC and Cmax results from the 500 simulations of the new formulations were represented. In vivo predicted profiles based on each formulation were plotted. Dissolution specification limits were calculated based on the formulations which successfully achieved the 90% CI.
Conclusions: A new method to establish in vitro dissolution specifications has been developed incorporating in vitro and in vivo interindividual and residual variability. This method is more restrictive, but guarantees bioequivalence standards for the new formulations developed based on the IVIVC previously established.
References:
[1] EMA, Guideline on quality of oral modified release products, 2014.
[2] FDA, Guidance for industry. Extended release oral dosage forms: development, evaluation and application of in vitro/in vivo correlations., 1997, US Department of Health and Human Services: Center for Drug Evaluation and Research (CDER).
Reference: PAGE 24 (2015) Abstr 3344 [www.page-meeting.org/?abstract=3344]
Poster: Drug/Disease modeling - Absorption & PBPK