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Challenge model of ...
Challenge model of TNFα turnover at varying LPS and drug provocations
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- Held, Felix (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper,Department of Mathematical Sciences,Chalmers tekniska högskola,Chalmers University of Technology,Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik (FCC),Fraunhofer-Chalmers Research Centre for Industrial Mathematics (FCC)
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- Hoppe, E. (författare)
- Grünenthal GmbH
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- Cvijovic, Marija, 1977 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper,Department of Mathematical Sciences,Chalmers tekniska högskola,Chalmers University of Technology
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- Jirstrand, Mats, 1968 (författare)
- Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik (FCC),Fraunhofer-Chalmers Research Centre for Industrial Mathematics (FCC)
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- Gabrielsson, J. (författare)
- Sveriges lantbruksuniversitet (SLU),Swedish University of Agricultural Sciences (SLU)
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(creator_code:org_t)
- 2019-02-18
- 2019
- Engelska.
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 46:3, s. 223-240
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Abstract
Ämnesord
Stäng
- A mechanism-based biomarker model of TNF α -response, including different external provocations of LPS challenge and test compound intervention, was developed. The model contained system properties (such as k t , k out ), challenge characteristics (such as k s , k LPS , K m,LPS , S max , SC 50 ) and test-compound-related parameters (I max , IC 50 ). The exposure to test compound was modelled by means of first-order input and Michaelis–Menten type of nonlinear elimination. Test compound potency was estimated to 20nM with a 70% partial reduction in TNF α -response at the highest dose of 30mg·kg −1 . Future selection of drug candidates may focus the estimation on potency and efficacy by applying the selected structure consisting of TNF α system and LPS challenge characteristics. A related aim was to demonstrate how an exploratory (graphical) analysis may guide us to a tentative model structure, which enables us to better understand target biology. The analysis demonstrated how to tackle a biomarker with a baseline below the limit of detection. Repeated LPS-challenges may also reveal how the rate and extent of replenishment of TNF α pools occur. Lack of LPS exposure-time courses was solved by including a biophase model, with the underlying assumption that TNF α -response time courses, as such, contain kinetic information. A transduction type of model with non-linear stimulation of TNF α release was finally selected. Typical features of a challenge experiment were shown by means of model simulations. Experimental shortcomings of present and published designs are identified and discussed. The final model coupled to suggested guidance rules may serve as a general basis for the collection and analysis of pharmacological challenge data of future studies. © 2019, The Author(s).
Ämnesord
- NATURVETENSKAP -- Matematik (hsv//swe)
- NATURAL SCIENCES -- Mathematics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- NATURVETENSKAP -- Matematik -- Sannolikhetsteori och statistik (hsv//swe)
- NATURAL SCIENCES -- Mathematics -- Probability Theory and Statistics (hsv//eng)
Nyckelord
- Challenge tests
- Experimental design
- Kinetic-dynamic modelling
- Non-linear mixed effects modelling
- Target biology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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