title: Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example.
abstract: The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media.
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Ragna
authors.initials: R
authors.lastname: Berthelsen
authors.affiliation: Department of Pharmacy, Uppsala University, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Sjögren
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Jacobsen
authors.affiliation: Global R&D, Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kristensen
authors.affiliation: Biologics and Pharmaceutical Sciences, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: AstraZeneca Pharmaceutics, R&D, Mölndal, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
authors.affiliation: Bioneer:FARMA, Department of Pharmacy, Universitetsparken 2, University of Copenhagen, Copenhagen 2100, Denmark. Electronic address: Anette.mullertz@sund.ku.dk.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D001682:Biological Availability; D003198:Computer Simulation; D018592:Cross-Over Studies; D005215:Fasting / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D000960:Hypolipidemic Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000960:Hypolipidemic Agents; D013501:Surface-Active Agents; D011345:Fenofibrate
keywords: Clinical data; Cremophor ELP; Fenofibrate (PubChem CID: 3339); GI-Sim absorption model; Immediate release tablets; In vivo–in vitro–in silico correlation; Mini paddle dissolution; Poloxamer 188, poloxamer 407 (PubChem CID: 24751); Sodium dodecyl sulfate (PubChem CID 342365); Surfactants