Combining species specific in vitro & in silico models to predict in vivo food effect in a preclinical stage – case study of Venetoclax

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dc.contributor.authorHenze, Laura J.
dc.contributor.authorKoehl, Niklas J.
dc.contributor.authorO'Shea, Joseph P.
dc.contributor.authorHolm, René
dc.contributor.authorVertzoni, Maria
dc.contributor.authorGriffin, Brendan T.
dc.contributor.funderHorizon 2020en
dc.contributor.funderH2020 Marie Skłodowska-Curie Actionsen
dc.date.accessioned2021-06-03T12:27:47Z
dc.date.available2021-06-03T12:27:47Z
dc.date.issued2021-04-15
dc.date.updated2021-06-03T12:19:21Z
dc.description.abstractThe pig has been increasingly used as a reliable preclinical model for assessing and predicting the in vivo bioavailability of different formulation strategies. Nevertheless, differences in the composition between porcine and human intestinal fluids, may impact on the solubility and dissolution behaviour of drugs, in particular BCS II/IV drugs. Recently, a porcine fasted simulated intestinal fluid (FaSSIFp) was developed to mimic the composition in the lumen of landrace pigs under fasted state conditions. In this work, we present the utilization of FaSSIFp to compare solubility against human FaSSIF & FeSSIF and further combine species specific in vitro testing with in silico predictive modelling. Venetoclax was chosen as a model drug, representing a BCS class IV drug, with a reported clinically significant positive food effect, where bioavailability is increased up to approximately five-fold when administered with a high-fat meal. Biorelevant species specific in vitro testing was a promising tool for integrating in vitro data into in silico models, using FaSSIFp resulted in reliable predictions of the plasma concentration profile in fasted pigs, based on a porcine physiologically based absorption model. The porcine physiologically based absorption model was used to prospectively simulate the impact of food on the bioavailability of venetoclax. The use of luminal solubility estimates in combination with dissolution data for venetoclax, measured in species specific simulated fluids, correctly predict the observed pig plasma concentration profile and food effect. Overall, integrating species specific in vitro – in silico models led to accurate prediction of in vivo absorption of venetoclax in a preclinical stage, which can support guidance in early decisions of drug product development. In addition, the study further demonstrated the utility of the pig model to predict the food effects of venetoclax in humans.en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid105840en
dc.identifier.citationHenze, L. J., Koehl, N. J., O'Shea, J. P., Holm, R., Vertzoni, M. and Griffin, B. T. (2021) 'Combining species specific in vitro & in silico models to predict in vivo food effect in a preclinical stage – case study of Venetoclax', European Journal of Pharmaceutical Sciences, 162, 105840 (9 pp). doi: 10.1016/j.ejps.2021.105840en
dc.identifier.doi10.1016/j.ejps.2021.105840en
dc.identifier.endpage9en
dc.identifier.issn0928-0987
dc.identifier.journaltitleEuropean Journal of Pharmaceutical Sciencesen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/11444
dc.identifier.volume162en
dc.language.isoenen
dc.publisherElsevieren
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.relation.urihttps://www.sciencedirect.com/science/article/pii/S0928098721001421
dc.rights© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectBCS IVen
dc.subjectFaSSIFen
dc.subjectFaSSIFpen
dc.subjectFood effecten
dc.subjectIn silicoen
dc.subjectIn vitroen
dc.subjectLandrace pigsen
dc.titleCombining species specific in vitro & in silico models to predict in vivo food effect in a preclinical stage – case study of Venetoclaxen
dc.typeArticle (peer-reviewed)en
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