title: Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments.
abstract: Novel formulations that overcome the solubility limitations of poorly water soluble drugs (PWSD) are becoming ever more critical to a drug development process inundated with these compounds. There is a clear need for developing bio-enabling formulation approaches to improve oral bioavailability for PWSD, but also to establish a range of predictive in vitro and in silico biopharmaceutics based tools for guiding formulation design and forecasting in vivo effects. The dual aim of this study was to examine the potential for a novel lipid based formulation, termed a lipidic dispersion, to enhance fasted state oral bioavailability of fenofibrate, while also assessing the predictive ability of biorelevant in vitro and in silico testing. Formulation as a lipidic dispersion improved both dissolution and solubilisation of fenofibrate through a combination of altered solid state characteristics and incorporation of solubilising lipidic excipients. These changes resulted in an increased rate of absorption and increased maximal plasma concentrations compared to a commercial, micronised product (Lipantil® Micro) in a pig model. Combination of biorelevant in vitro measurements with in silico physiologically based pharmacokinetic (PBPK) modelling resulted in an accurate prediction of formulation performance and forecasts a reduction in food effects on fenofibrate bioavailability through maximising its fasted state dissolution.
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: O'Shea
authors.affiliation: Faculty of Pharmacy, Minia University, Egypt.
authors.forename: Waleed
authors.initials: W
authors.lastname: Faisal
authors.affiliation: Department of Physiology, University College Cork, Ireland.
authors.forename: Therese
authors.initials: T
authors.lastname: Ruane-O'Hora
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Devine
authors.affiliation: Institut für Pharmazeutische Technologie, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Kostewicz
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland. Electronic address: brendan.griffin@ucc.ie.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001682:Biological Availability; D019295:Computational Biology; D018592:Cross-Over Studies; D004339:Drug Compounding; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry; D005103:Expert Systems; D011345:Fenofibrate / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D000960:Hypolipidemic Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D000069463:Olive Oil / Q000737:chemistry*; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D011897:Random Allocation; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*; D034421:Sus scrofa
chemical_list: D005079:Excipients; D000960:Hypolipidemic Agents; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles; D011136:Polysorbates; D013501:Surface-Active Agents; C022131:cremophor; D011092:Polyethylene Glycols; D011205:Povidone; D011345:Fenofibrate
keywords: Biorelevant dissolution testing; Fenofibrate; Food effect; In vitro in vivo correlations (IVIVC); Lipid based formulations; Physiologically based pharmacokinetic modelling; Pig model; Poorly water soluble drugs (PWSD)