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University of Otago

1. Gulati, Abhishek. Applications of pharmacometric methods to systems pharmacology .

Degree: 2013, University of Otago

Computational techniques are now being used to simulate virtually every facet of drug discovery and development. Attempts are being made to carry out a full computational evaluation at each step to avoid the failure of a large number of molecules at various stages of the drug development process. Use of computational approaches for a better understanding of the behavior of drugs in the human body has resulted in models that scale molecular events to intact organ systems and from events that occur in micro-seconds to an entire human lifetime. Mathematical models that relate the pharmacology of drug(s) in biological system(s) are known as systems pharmacology models and are usually very complex as well as complicated and are often described by hundreds of equations. Applications of existing systems pharmacology models have been limited to answer “what-if” style questions using simulations. The overarching aim of the work carried out in this thesis was to apply pharmacometric methodologies to an existing blood coagulation systems pharmacology model for use in two different aspects of drug development. It focused on identification and evaluation of a biomarker for monitoring enoxaparin therapy and on simplification of the systems model for use in development of a population pharmacokinetic-pharmacodynamic (PKPD) model for fibrinogen. In the first part of this thesis, simulations using the systems model identified that a clotting time test based on factor Xa (TenaCT) had the potential to be used to assess the effect of enoxaparin on the clotting system. This Xa based test produced clotting times that are likely to be manageable in the clinic and an in vitro evaluation using plasma from a single healthy volunteer demonstrated proof-of-mechanism of the test. A pilot study, designed using adaptive DP-optimality, was then carried out to evaluate the TenaCT test. The pilot study has provided a range of sets of values of the activating agent factor Xa and the co-factor Actin FS; where using any of these values would give a high probability of a successful proof-of-concept study. These sets of values were identified using a response surface modelling technique that utilized the clotting time surfaces at 4 different enoxaparin concentrations to obtain various Xa-Actin FS concentrations that determined the overall success of the TenaCT test. In the second part of this thesis, simulations using the systems model provided a reasonable prediction of the observed concentrations of clotting factors over time in patients bitten by Australian elapid snakes. The model predictions suggested a higher consumption of factors (fibrinogen, II and IX in particular) in patients with complete venom induced consumption coagulopathy (VICC) compared to those with partial VICC. The model also predicted that snakes with “Xa-like” venoms may produce a less severe VICC than snakes with “Xa:Va like” venoms. Time for recovery from snakebite is often based on recovery of fibrinogen. A simplification of the systems model was necessary to provide the… Advisors/Committee Members: Duffull, Stephen (advisor).

Subjects/Keywords: pharmacometrics; systems pharmacology; mathematical modelling; coagulation; pharmacokinetics-pharmacodynamics; enoxaparin; clotting time test; adaptive design; DP-optimality; response surface modelling; proper lumping; identifiability; fibrinogen; Australian elapids

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

APA (6th Edition):

Gulati, A. (2013). Applications of pharmacometric methods to systems pharmacology . (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/4169

Chicago Manual of Style (16th Edition):

Gulati, Abhishek. “Applications of pharmacometric methods to systems pharmacology .” 2013. Doctoral Dissertation, University of Otago. Accessed September 23, 2020. http://hdl.handle.net/10523/4169.

MLA Handbook (7th Edition):

Gulati, Abhishek. “Applications of pharmacometric methods to systems pharmacology .” 2013. Web. 23 Sep 2020.

Vancouver:

Gulati A. Applications of pharmacometric methods to systems pharmacology . [Internet] [Doctoral dissertation]. University of Otago; 2013. [cited 2020 Sep 23]. Available from: http://hdl.handle.net/10523/4169.

Council of Science Editors:

Gulati A. Applications of pharmacometric methods to systems pharmacology . [Doctoral Dissertation]. University of Otago; 2013. Available from: http://hdl.handle.net/10523/4169

.