Computational modeling of the pharmacokinetics and pharmacodynamics of selected xenobiotics
| dc.contributor.author | Zurlinden, Todd J., author | |
| dc.contributor.author | Reisfeld, Brad, advisor | |
| dc.contributor.author | Hays, Sean, committee member | |
| dc.contributor.author | Shipman, Patrick, committee member | |
| dc.contributor.author | Munsky, Brian, committee member | |
| dc.date.accessioned | 2017-01-04T22:59:16Z | |
| dc.date.available | 2017-01-04T22:59:16Z | |
| dc.date.issued | 2016 | |
| dc.description.abstract | The determination of important endpoints in toxicology and pharmacology continues to involve the acquisition of large amounts of data through resource-intensive experimental studies involving a large number of resources. Because of this, only a small fraction of chemicals in the environment and marketplace can reasonably be evaluated for safety, and many promising drug candidates must be eliminated from consideration based on inadequate evaluation. Promisingly, advances in biologically-based computational models are beginning to allow researchers to estimate these endpoints and make useful extrapolations using a limited set of experimental data. The work described in this dissertation examined how computational models can provide meaningful insight and quantitation of important pharmacological and toxicological endpoints related to toxicity and pharmacological efficacy. To this end, physiologically-based pharmacokinetic and pharmacodynamic models were developed and applied for several pharmaceutical agents and environmental toxicants to predict significant, and diverse, biological endpoints. First, physiologically-based modeling allowed for the evaluation of various dosing regimens of rifapentine, a drug that is showing great promise for the treatment of tuberculosis, by comparing lung-specific concentration predictions to experimentally-derived thresholds for antibacterial activity. Second, physiologically-based pharmacokinetic modeling, coupled with Bayesian inference, was used as part of a methodology to characterize genetic differences in acetaminophen pharmacokinetics and also to help clinicians predict an ingested dose of this drug under overdose conditions. Third, a methodology for using physiologically-based pharmacokinetic modeling to predict health-based cognitive endpoints was demonstrated for chronic exposure to chlorpyrifos, an organophosphorus insecticide. The environmental public health indicators derived from this work allowed for biomarkers of exposure to be used to predict neurobehavioral changes following long-term exposure to this chemical. Finally, computational modeling was used to develop a mechanistically-plausible pharmacodynamic model for hepatoprotective and pro-inflammatory events to relate trichloroethylene dosing conditions to observed pathologies associated with auto-immune hepatitis. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | Zurlinden_colostate_0053A_13947.pdf | |
| dc.identifier.uri | http://hdl.handle.net/10217/178903 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | biological modeling | |
| dc.subject | pharmacodynamic modeling | |
| dc.subject | Bayesian inference | |
| dc.subject | physiologically-based pharmacokinetic modeling | |
| dc.subject | computational pharmacology | |
| dc.title | Computational modeling of the pharmacokinetics and pharmacodynamics of selected xenobiotics | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Chemical and Biological Engineering | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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