Advanced search options

Advanced Search Options 🞨

Browse by author name (“Author name starts with…”).

Find ETDs with:

in
/  
in
/  
in
/  
in

Written in Published in Earliest date Latest date

Sorted by

Results per page:

You searched for subject:( QSP models). One record found.

Search Limiters

Last 2 Years | English Only

No search limiters apply to these results.

▼ Search Limiters


University of Otago

1. Siripuram, Vijay Kumar. Understanding azathioprine metabolism using a systems pharmacology approach .

Degree: University of Otago

Quantitative systems pharmacology (QSP) modelling, being an integral part of pharmacometrics, is attracting a great amount of attention in drug development and clinical therapy as QSP models are used to identify drug targets and biomarkers of response. The QSP model based approach was used to address the clinical challenges with azathioprine dosing in inflammatory bowel disease. The Overarching aim of the thesis was to understand unknown mechanism to toxicities associated with azathioprine metabolism using a QSP approach. However some unanticipated challenges resulted during development of the azathioprine QSP model which, ultimately, was found to not be able to describe the various clinical scenarios. These challenges did, however, provide an opportunity to understand some issues that might arise during QSP model development and develop methods to solve them. A 30 state QSP model was developed for azathioprine metabolism based on known purine metabolic pathways supported by literature and expert opinion (Chapter 2). The model provided a good prediction of both extraceullar and intracellular metabolite formation after azathioprine dosing for the typical clinical scenario. The model was then used to test the existing hypotheses for abnormal enzyme activities for two atypical clinical scenarios. The results indicated that the model could not reflect the reference concentrations for either atypical scenario. This raised the following questions: whether the hypothesised enzymes that were considered to be responsible for the atypical clinical scenarios were not responsible, whether the model was correct but the set of parameters for the whole system were incorrect or whether the structure was incorrect. The first two questions were addressed simultaneously by proposing a combined question, does a set of parameter values exist that could describe the typical and both atypical scenarios. If a set existed then the model was described as being complete. To address the model completeness issue in a QSP framework a global search algorithm was developed to optimise the model parameter values across all pathways and altered enzyme activity for the atypical scenarios (Chapter 3). No sets of parameter values were found that adequately described the reference data from both the typical and both atypical scenarios. The model was therefore deemed to be incomplete. The conclusion from this evaluation was that the model structure was incorrect. Given the outcome from the search for model completeness, it was necessary to determine alternative structures that could solve for the reference data. In the next work (Chapter 4) a search across potential model structures was implemented using simulated annealing. A method was developed that used a combination of binary logic and continuous flux to search across model structures and parameter values, respectively. The search was found to be stable and was unaffected by dimensionality and identifiability issues (within the confines of the models evaluated). Four alternative model… Advisors/Committee Members: Duffull, Stephen (advisor).

Subjects/Keywords: Pharmacometrics; Population pharmacokinetics; azathioprine; modelling and simulation; identifiability; simulated annealing; QSP models

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Siripuram, V. K. (n.d.). Understanding azathioprine metabolism using a systems pharmacology approach . (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/9474

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16th Edition):

Siripuram, Vijay Kumar. “Understanding azathioprine metabolism using a systems pharmacology approach .” Doctoral Dissertation, University of Otago. Accessed August 07, 2020. http://hdl.handle.net/10523/9474.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7th Edition):

Siripuram, Vijay Kumar. “Understanding azathioprine metabolism using a systems pharmacology approach .” Web. 07 Aug 2020.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Siripuram VK. Understanding azathioprine metabolism using a systems pharmacology approach . [Internet] [Doctoral dissertation]. University of Otago; [cited 2020 Aug 07]. Available from: http://hdl.handle.net/10523/9474.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Siripuram VK. Understanding azathioprine metabolism using a systems pharmacology approach . [Doctoral Dissertation]. University of Otago; Available from: http://hdl.handle.net/10523/9474

Note: this citation may be lacking information needed for this citation format:
No year of publication.

.