Supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax

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dc.contributor.authorKoehl, Niklas J.
dc.contributor.authorHenze, Laura J.
dc.contributor.authorKuentz, Martin
dc.contributor.authorHolm, René
dc.contributor.authorGriffin, Brendan T.
dc.contributor.funderHorizon 2020en
dc.date.accessioned2020-07-10T08:46:33Z
dc.date.available2020-07-10T08:46:33Z
dc.date.issued2020-06-18
dc.date.updated2020-07-10T08:06:42Z
dc.description.abstractIncreasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid564en
dc.identifier.citationKoehl, N. J., Henze, L. J., Kuentz, M., Holm, R. and Griffin, B. T. (2020) 'Supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax', Pharmaceutics, 12(6), 564 (20pp). doi: 10.3390/pharmaceutics12060564en
dc.identifier.doi10.3390/pharmaceutics12060564en
dc.identifier.endpage20en
dc.identifier.issn1999-4923
dc.identifier.issued6en
dc.identifier.journaltitlePharmaceuticsen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/10228
dc.identifier.volume12en
dc.language.isoenen
dc.publisherMDPIen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::MSCA-ITN-ETN/674909/EU/Pharmaceutical Education And Research with Regulatory Links: Innovative drug development strategies and regulatory tools tailored to facilitate earlier access to medicines/PEARRLen
dc.rights© 2020, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectAmorphous solubilityen
dc.subjectLandrace pigsen
dc.subjectLipid suspensionsen
dc.subjectLipid-based formulationen
dc.subjectSEDDSen
dc.subjectSelf-emulsifying drug delivery system Super-SNEDDSen
dc.subjectSupersaturated lipid-based formulationsen
dc.subjectSupersaturationen
dc.subjectVenetoclaxen
dc.titleSupersaturated lipid-based formulations to enhance the oral bioavailability of venetoclaxen
dc.typeArticle (peer-reviewed)en
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