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Dose–response-time modelling : second-generation turnover model with integral feedback control
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Andersson, Robert, Jirstrand, Mats, Peletier, Lambertus, Chappell, M. J. (Michael J.), Evans, Neil D. and Gabrielsson, Johan (2016) Dose–response-time modelling : second-generation turnover model with integral feedback control. European Journal of Pharmaceutical Sciences, 81 . pp. 189-200. doi:10.1016/j.ejps.2015.10.018 ISSN 0928-0987.
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Official URL: http://dx.doi.org/10.1016/j.ejps.2015.10.018
Abstract
This study presents a dose-response-time (DRT) analysis based on a large preclinical biomarker dataset on the interaction between nicotinic acid (NiAc) and free fatty acids (FFA). Data were collected from studies that examined different rates, routes, and modes of NiAc provocations on the FFA time course. All information regarding the exposure to NiAc was excluded in order to demonstrate the utility of a DRT model. Special emphasis was placed on the selection process of the biophase model. An inhibitory Imax-model, driven by the biophase amount, acted on the turnover rate of FFA. A second generation NiAc/FFA model, which encompasses integral (slow buildup of tolerance - an extension of the previously used NiAc/FFA turnover models) and moderator (rapid and oscillatory) feedback control, was simultaneously fitted to all time courses in normal rats. The integral feedback control managed to capture an observed 90% adaptation (i.e., almost a full return to baseline) when 10 days constant-rate infusion protocols of NiAc were used. The half-life of the adaptation process had a 90% prediction interval between 3.5-12 in the present population. The pharmacodynamic parameter estimates were highly consistent when compared to an exposure-driven analysis, partly validating the DRT modelling approach and suggesting the potential of DRT analysis in areas where exposure data are not attainable. Finally, new numerical algorithms, which rely on sensitivity equations to robustly and efficiently compute the gradients in the parameter optimization, were successfully used for the mixed-effects approach in the parameter estimation.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RA Public aspects of medicine | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering | ||||||||
| Library of Congress Subject Headings (LCSH): | Dose-response relationship (Biochemistry), Niacin, Fatty acids | ||||||||
| Journal or Publication Title: | European Journal of Pharmaceutical Sciences | ||||||||
| Publisher: | Elsevier BV | ||||||||
| ISSN: | 0928-0987 | ||||||||
| Official Date: | 1 January 2016 | ||||||||
| Dates: |
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| Volume: | 81 | ||||||||
| Page Range: | pp. 189-200 | ||||||||
| DOI: | 10.1016/j.ejps.2015.10.018 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
| Date of first compliant deposit: | 22 January 2018 | ||||||||
| Date of first compliant Open Access: | 23 January 2018 | ||||||||
| RIOXX Funder/Project Grant: |
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