title: In vitro lipolysis data does not adequately predict the in vivo performance of lipid-based drug delivery systems containing fenofibrate.
abstract: The present study investigated the utility of in vitro lipolysis performance indicators drug solubilization and maximum supersaturation ratio (SR(M)) for their predictive use for the in vivo performance in a minipig model. The commercial Lipanthyl formulation and a series of LbDDS based on identical self-nanoemulsifying drug delivery systems (SNEDDS) containing 200 mg of fenofibrate, either dissolved or suspended, were subjected to combined gastric (pH 2) and intestinal (pH 6.5) in vitro lipolysis. Based on the solubilization profiles and SRM the rank-order SNEDDS (75% drug load) > super-SNEDDS (150% drug load, dissolved) = SNEDDS suspension (150% drug load, partially suspended) > Lipanthyl was established, with an increased likelihood of drug precipitation above SR(M) > 3. The in vitro performance, however, was not reproduced in vivo in a minipig model as the mean plasma concentration over time curves of all LbDDS were comparable, independent of the initial physical state of the drug. There was no correlation between the area under the solubilization-time curves (AUC(in vitro)) of the intestinal step and the AUC(in vivo). The study suggests careful interpretation of in vitro performance criteria and revision of LbDDS optimization towards increased solubilization.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100, Denmark.
authors.forename: Nicky
authors.initials: N
authors.lastname: Thomas
authors.forename: Katharina
authors.initials: K
authors.lastname: Richter
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Pedersen
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D005079:Excipients; D011345:Fenofibrate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D013535:Suspensions; D013552:Swine; D013556:Swine, Miniature
chemical_list: D005079:Excipients; D000960:Hypolipidemic Agents; D008055:Lipids; D013535:Suspensions; D011345:Fenofibrate