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dc.contributor.authorEigenmann, Miro Julianen_US
dc.contributor.authorKarlsen, Tine Veronicaen_US
dc.contributor.authorKrippendorff, Ben-Fillippoen_US
dc.contributor.authorTenstad, Olaven_US
dc.contributor.authorFronton, Ludivineen_US
dc.contributor.authorOtteneder, Michael B.en_US
dc.contributor.authorWiig, Helgeen_US
dc.date.accessioned2019-04-26T12:46:15Z
dc.date.available2019-04-26T12:46:15Z
dc.date.issued2017-12
dc.PublishedEigenmann, Karlsen TV, Krippendorff, Tenstad O, Fronton, Otteneder, Wiig H. Interstitial IgG antibody pharmacokinetics assessed by combined in vivo- and physiologically-based pharmacokinetic modelling approaches. Journal of Physiology. 2017;595(24):7311-7330eng
dc.identifier.issn0022-3751
dc.identifier.issn1469-7793
dc.identifier.urihttps://hdl.handle.net/1956/19422
dc.description.abstractFor most therapeutic antibodies, the interstitium is the target space. Although experimental methods for measuring antibody pharmacokinetics (PK) in this space are not well established, thus making quantitative assessment difficult, the interstitial antibody concentration is assumed to be low. In the present study, we combined direct quantification of antibodies in the interstitial fluid with a physiologically‐based PK (PBPK) modelling approach, with the aim of better describing the PK of monoclonal antibodies in the interstitial space of different tissues. We isolated interstitial fluid by tissue centrifugation and conducted an antibody biodistribution study in mice, measuring total tissue and interstitial concentrations in selected tissues. Residual plasma, interstitial volumes and lymph flows, which are important PBPK model parameters, were assessed in vivo. We could thereby refine the PBPK modelling of monoclonal antibodies, better interpret antibody biodistribution data and more accurately predict their PK in the different tissue spaces. Our results indicate that, in tissues with discontinuous capillaries (liver and spleen), interstitial concentrations are reflected by the plasma concentration. In tissues with continuous capillaries (e.g. skin and muscle), ∼50–60% of the plasma concentration is found in the interstitial space. In the brain and kidney, on the other hand, antibodies are restricted to the vascular space. Our data may significantly impact the interpretation of biodistribution data of monoclonal antibodies and might be important when relating measured concentrations to a therapeutic effect. By contrast to the view that the antibody distribution to the interstitial space is limited, using direct measurements and model‐based data interpretation, we show that high antibody interstitial concentrations are reached in most tissues.en_US
dc.language.isoengeng
dc.publisherWileyeng
dc.titleInterstitial IgG antibody pharmacokinetics assessed by combined in vivo- and physiologically-based pharmacokinetic modelling approachesen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2018-09-14T10:43:13Z
dc.description.versionacceptedVersionen_US
dc.rights.holderCopyright 2017 The Authors. The Journal of Physiology
dc.identifier.doihttps://doi.org/10.1113/jp274819
dc.identifier.cristin1547731
dc.source.journalJournal of Physiology
dc.relation.projectNorges forskningsråd: 262079


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