Combining biorelevant "in vitro" and "in silico" tools to simulate and better understand the "in vivo" performance of a nano-sized formulation of aprepitant in the fasted and fed states

  • Introduction: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range. Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature. Results: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80 mg and 125 mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb. Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Author:Chara Litou, Nikunjkumar Patel, David B. Turner, Edmund Kostewicz, Martin Kuentz, Karl J. Box, Jennifer B. DressmanGND
Place of publication:Frankfurt am Main
Document Type:Preprint
Date of Publication (online):2019/09/08
Year of first Publication:2019
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Creating Corporation:Johann Wolfgang Goethe-Universität Frankfurt am Main
Release Date:2019/08/13
Tag:PBPK; aprepitant; bio-enabling formulations; modeling and simulation; nano-sized drugs
Page Number:40
Running Title: PBPK modeling of aprepitant in the fasted and fed state
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoDeutsches Urheberrecht