title: In vitro models for the prediction of in vivo performance of oral dosage forms.
abstract: Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract.
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Kostewicz
authors.affiliation: Department of Global Medicines Development, AstraZeneca R&D, S-431 83 Mölndal, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
authors.affiliation: Drug Product Development, Pharmaceutical Development and Manufacturing Sciences, Janssen Research and Development, Johnson & Johnson, Beerse, Belgium.
authors.forename: Marcus
authors.initials: M
authors.lastname: Brewster
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.affiliation: Product Development, GlaxoSmithKline R&D, Harlow, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Butler
authors.affiliation: Department of Global Medicines Development, AstraZeneca R&D, S-431 83 Mölndal, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Carlert
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AstraZeneca R&D, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dickinson
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dressman
authors.affiliation: Biologics and Pharmaceutical Science, H.Lundbeck A/S, Ottiliavej 9, DK 2500 Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Klein
authors.affiliation: Development Laboratories, MSD, Hoddesdon, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Mann
authors.affiliation: Drug Product Design, Pfizer PGRD, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: McAllister
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: Mans
authors.initials: M
authors.lastname: Minekus
authors.affiliation: Material Science and Early Characterization, Research Center Aprath, Bayer Pharma AG, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Muenster
authors.affiliation: Pharmaceutical Design and Drug Delivery, University of Copenhagen, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Verwei
authors.affiliation: Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Greifswald, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium. Electronic address: patrick.augustijns@pharm.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods*; D004304:Dosage Forms; D005769:Gastrointestinal Motility; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D010602:Pharmacopoeias as Topic; D012995:Solubility
chemical_list: D004304:Dosage Forms; D004364:Pharmaceutical Preparations
keywords: Biorelevant; In vitro evaluation; In vivo biopharmaceutical performance; Innovative Medicines Initiative (IMI); Oral Biopharmaceutical Tools (OrBiTo); Oral drug formulations