In silico, in vitro, and in vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax

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dc.contributor.authorKoehl, Niklas J.
dc.contributor.authorHenze, Laura J.
dc.contributor.authorBennett-Lenane, Harriet
dc.contributor.authorFaisal, Waleed
dc.contributor.authorPrice, Daniel J.
dc.contributor.authorHolm, René
dc.contributor.authorKuentz, Martin
dc.contributor.authorGriffin, Brendan T.
dc.contributor.funderHorizon 2020en
dc.date.accessioned2021-11-12T09:50:32Z
dc.date.available2021-11-12T09:50:32Z
dc.date.issued2021-04-23
dc.date.updated2021-11-10T09:39:32Z
dc.description.abstractThe concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationKoehl, N.J., Henze, L. J., Bennett-Lenane, H., Faisal, W., Price, D. J., Holm, R., Kuentz, M. and Griffin, B. T. (2021) 'In silico, in vitro, and in vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax', Molecular Pharmaceutics, 18(6), pp. 2174-2188. doi: 10.1021/acs.molpharmaceut.0c00645en
dc.identifier.doi10.1021/acs.molpharmaceut.0c00645en
dc.identifier.eissn1543-8392
dc.identifier.endpage2188en
dc.identifier.issn1543-8384
dc.identifier.issued6en
dc.identifier.journaltitleMolecular Pharmaceuticsen
dc.identifier.startpage2174en
dc.identifier.urihttps://hdl.handle.net/10468/12204
dc.identifier.volume18en
dc.language.isoenen
dc.publisherACS Publicationsen
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© 2021, the Authors. Published by the American Chemical Society. This is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectPrecipitation inhibitoren
dc.subjectLipid based formulationen
dc.subjectVenetoclaxen
dc.subjectSEDDSen
dc.subjectSNEDDSen
dc.subjectSMEDDSen
dc.subjectLipid suspensionen
dc.subjectPolymersen
dc.subjectSuper-SNEDDSen
dc.subjectSupersaturationen
dc.subjectSuper-SMEDDSen
dc.subjectSupersaturating drug delivery systemsen
dc.titleIn silico, in vitro, and in vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclaxen
dc.typeArticle (peer-reviewed)en
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