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dc.contributor.advisorForrest, M. Laird
dc.contributor.authorVarkhede, Ninad
dc.date.accessioned2019-05-10T17:05:09Z
dc.date.available2019-05-10T17:05:09Z
dc.date.issued2018-12-31
dc.date.submitted2018
dc.identifier.otherhttp://dissertations.umi.com/ku:16181
dc.identifier.urihttp://hdl.handle.net/1808/27855
dc.description.abstractSubcutaneous (SC) route is important for administration of various therapeutic proteins (TPs) like monoclonal antibodies (mAbs), human growth hormone (hGH), insulin, and recombinant subunit vaccines. The SC route has advantages like shorter clinical visits for patients, the possibility of self-administration, and its less invasive nature compared to the intravenous (IV) route. However, SC route has a challenge of incomplete bioavailability for various TPs, especially mAbs (52-80%). After SC administration, the mAbs travel through the lymphatic vessels and lymph nodes (LNs) before reaching the systemic circulation. Proteolysis at the SC injection site and within the lymphatic system may be partially responsible for the reduced bioavailability of mAbs. Chapter 2 of this dissertation describes a top-down mAb physiologically based pharmacokinetic (PBPK) model which was used to estimate the lymphatic trunk-LN clearance using the human SC pharmacokinetic (PK) data from published clinical trials. Iron oxide nanoparticles (IONPs) may originate from equipment used in the manufacturing of TPs or from needles during the SC injection. The IONPs may alter the secondary structure and the degree of oxidation of TPs. Therefore, Chapter 3 of this dissertation looks at the effect of IONPs on the TP stability. In Chapter 4, midazolam (MDZ) metabolism and PK were reported in the healthy and inflammatory disease condition in mice. Finally, a bottom-up minimal PBPK model was used to predict MDZ PK in the disease state.
dc.format.extent158 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmaceutical sciences
dc.subjectInflammation
dc.subjectLymphatics
dc.subjectMonoclonal antibody
dc.subjectPBPK modelling
dc.subjectPharmacokinetics
dc.subjectRat growth hormone
dc.titleUnderstanding the metabolic processes and degradation of therapeutic proteins after subcutaneous administration
dc.typeDissertation
dc.contributor.cmtememberKrise, Jeffrey
dc.contributor.cmtememberSchöneich, Christian
dc.contributor.cmtememberWang, Michael
dc.contributor.cmtememberDhar, Prajnaparamita
dc.thesis.degreeDisciplinePharmaceutical Chemistry
dc.thesis.degreeLevelPh.D.
dc.identifier.orcidhttps://orcid.org/0000-0002-9733-022X
dc.rights.accessrightsopenAccess


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