title: Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential.
abstract: BACKGROUND
  The purpose of this study was (i) to evaluate the gastrointestinal behavior of micro- and nanosized fenofibrate in humans and (ii) to develop a simple yet qualitatively predictive in vitro setup that simulates the observed absorption-determining factors.
  
  
  METHODS
  Commercially available micro- and nanoparticles of fenofibrate (Lipanthyl® and Lipanthylnano®, respectively) were administered orally to five healthy volunteers in fasting and postprandial conditions. Intraluminal and systemic drug concentrations were determined as reference data for the development of a predictive in vitro setup. To capture the observed solubility/permeability interplay, in vitro dissolution testing was performed in the presence of a permeation bag with sink conditions.
  
  
  RESULTS
  In fasting conditions, intake of nanosized fenofibrate generated increased duodenal concentrations compared to microsized fenofibrate, which was reflected in an improved systemic exposure. In postprandial conditions, duodenal concentrations were greatly enhanced for both formulations, however without an accompanying increase in systemic exposure. It appeared that micellar encapsulation of the highly lipohilic fenofibrate limited its potential to permeate from fed state intestinal fluids. To capture these in vivo observations in an in vitro setup, classic dissolution testing was combined with permeation assessment into a permeation bag with sink conditions. In case of fasting conditions, the dissolution/permeation approach allowed for an improved discriminative power between micro- and nanosized fenofibrate by better simulating the dynamic interplay of dissolution and absorption. In case of postprandial conditions, the observed solubility-permeability interplay could be simulated using the dissolution/permeation approach in combination with biorelevant media (FeSSGFFortimel and FeSSIF-V2) to mimic micellar entrapment and reduced permeation potential of fenofibrate.
  
  
  CONCLUSIONS
  For the first time, reduced permeation of a lipophilic drug despite increased intraluminal concentrations, was demonstrated in humans. Dissolution testing using biorelevant media in combination with permeation assessment into a sink permeation bag appeared to be a simple yet pragmatic approach to capture this solubility-permeability interplay in early formulation evaluation.
authors.affiliation: Drug Delivery & Disposition, KU Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Hens
authors.affiliation: Drug Delivery & Disposition, KU Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium.
authors.forename: Maura
authors.initials: M
authors.lastname: Corsetti
authors.affiliation: Drug Delivery & Disposition, KU Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium. Electronic address: patrick.augustijns@pharm.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D011345:Fenofibrate / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008863:Microspheres; D053758:Nanoparticles; D012995:Solubility
chemical_list: D000960:Hypolipidemic Agents; D011345:Fenofibrate
keywords: Clinical study; Dialysis; Dissolution; Fenofibrate; Microparticles; Nanoparticles; Permeation; Solubility–permeability interplay