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Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach.
Eur J Pharm Biopharm. 2013 Nov; 85(3 Pt B):1274-84.EJ

Abstract

Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C(max) and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro-in silico-in vivo approach.

Authors+Show Affiliations

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address: fei@em.uni-frankfurt.de.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23500116

Citation

Fei, Yang, et al. "Analysis of the Enhanced Oral Bioavailability of Fenofibrate Lipid Formulations in Fasted Humans Using an in Vitro-in Silico-in Vivo Approach." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 85, no. 3 Pt B, 2013, pp. 1274-84.
Fei Y, Kostewicz ES, Sheu MT, et al. Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach. Eur J Pharm Biopharm. 2013;85(3 Pt B):1274-84.
Fei, Y., Kostewicz, E. S., Sheu, M. T., & Dressman, J. B. (2013). Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 85(3 Pt B), 1274-84. https://doi.org/10.1016/j.ejpb.2013.03.001
Fei Y, et al. Analysis of the Enhanced Oral Bioavailability of Fenofibrate Lipid Formulations in Fasted Humans Using an in Vitro-in Silico-in Vivo Approach. Eur J Pharm Biopharm. 2013;85(3 Pt B):1274-84. PubMed PMID: 23500116.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach. AU - Fei,Yang, AU - Kostewicz,Edmund S, AU - Sheu,Ming-Thau, AU - Dressman,Jennifer B, Y1 - 2013/03/14/ PY - 2012/11/06/received PY - 2013/02/14/revised PY - 2013/03/02/accepted PY - 2013/3/19/entrez PY - 2013/3/19/pubmed PY - 2014/8/13/medline KW - Biorelevant dissolution tests KW - Fenofibrate KW - Lipid-based formulation KW - Oral absorption KW - Permeability KW - Physiologically based pharmacokinetic model SP - 1274 EP - 84 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 85 IS - 3 Pt B N2 - Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C(max) and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro-in silico-in vivo approach. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/23500116/Analysis_of_the_enhanced_oral_bioavailability_of_fenofibrate_lipid_formulations_in_fasted_humans_using_an_in_vitro_in_silico_in_vivo_approach_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0939-6411(13)00083-0 DB - PRIME DP - Unbound Medicine ER -