<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Integration of pharmacokinetic and\r\nintracellular models of interferon\r\nadministration and induced responses"^^ . "A thorough understanding of drug-target relationships is essential in preclinical\r\nand clinical translation studies. However, there is a gap of knowledge in the quantitative\r\nunderstanding of dose-response relationships at the target site. To fill that\r\ngap, a particularly promising approach is quantitative systems pharmacology (QSP)\r\nwhere, mechanistic and hence comprehensive models of dose-effect relationships\r\nare used to guide the design of clinical and translational studies.\r\nIn this thesis, I present for the first time a QSP approach for a therapeutic protein, interferon\r\nalpha (IFN-a), by coupling physiologically based pharmacokinetic (PBPK)\r\nmodels at the whole-body level with intracellular models of signal transduction in\r\nthe liver. Whole-body distribution models of an injected dose of IFN-a calibrated to\r\nquantitative measurements of the plasma concentration are established for humans\r\nand mice. They are then coupled to mechanistic intracellular models of the triggered\r\nJAK/STAT signalling cascade that describes the dynamic response in the expression\r\nof the antiviral mRNAc of IRF9 for humans and antiviral protein Mx2 for mice on\r\nthe cellular scale. By doing so, I am able to establish the quantitative dose-effect relationship\r\nof the injected IFN-a dose to the responding interferon stimulated genes\r\n(ISGs) triggered at the target site, the liver.\r\nThe established multi-scale physiologically based pharmacokinetic/pharmacodynamic\r\n(PBPK/PD) model of human predict a reduced response of IRF9 mRNAc\r\nto IFN-a under physiological in vivo conditions as compared to in vitro. The QSP\r\nmodel also elicits the large impact of the IFN-receptors on the clearance of IFN-a in\r\nthe liver, thus, not only providing mechanistic insights into the pharmacodynamic\r\n(PD) response but also elucidating the influence of receptor variability on the response.\r\nAlthough IFN-a is specifically used in humans, in preclinical studies, it is also tested\r\nin mice for understanding the medical impact of IFN-a for other diseases. Therefore,\r\nI elaborate an analogous QSP model for the IFN-a response in mice to illustrate possibilities\r\nof model-based cross species translation. Like the human model, a whole\r\nbody PBPK/PD mouse model was also established to follow the response of antiviral\r\nprotein Mx2. The model clarified the differences between the pharmacokinetics\r\nof human and murine IFN-a injection in mice and will support quantitative crossspecies\r\nextrapolation in the future.\r\nFinally, as heterogeneity in ISGs reflects inter-cell variability in response to IFN-a, I\r\nstudy the impact of sources of this heterogeneity by implementing the mechanistic\r\nstochastic model of the JAK/STAT signalling pathway. The model was developed\r\non the basis of time-resolved flow cytometry data of two ISGs, MxA and IFIT1, in\r\nHuh7.5 cells. The model analysed intrinsic variability in the concentration of the\r\nmolecules of the pathway and generated a graded response of MxA and IFIT1 instead\r\nof an all-or-none response. Ultimately, the model concludes that the stochasticity\r\nin the initiation of the signalling pathway, i.e., at the receptor level, can be\r\nbuffered by the system and a more robust response of ISGs, MxA and IFIT1 is induced."^^ . "2019" . . . . . . . "Priyata"^^ . "Kalra"^^ . "Priyata Kalra"^^ . . . . . . "Integration of pharmacokinetic and\r\nintracellular models of interferon\r\nadministration and induced responses (PDF)"^^ . . . "Priyata_Thesis_eversion.pdf"^^ . . . "Integration of pharmacokinetic and\r\nintracellular models of interferon\r\nadministration and induced responses (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #27362 \n\nIntegration of pharmacokinetic and \nintracellular models of interferon \nadministration and induced responses\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .