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Deciphering drug dosing and response in special patient populations

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TitleInfo
Title
Deciphering drug dosing and response in special patient populations
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Brunetti
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Luigi
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Luigi Brunetti
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author
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Kagan
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Leonid
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Leonid Kagan
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Advisory Committee
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chair
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Colaizzi
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John L
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John L Colaizzi
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Advisory Committee
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internal member
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Minko
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Tamara
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Tamara Minko
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Advisory Committee
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internal member
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Sturgill
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Marc
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Marc Sturgill
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Advisory Committee
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internal member
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Gershkovich
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Pavel
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Pavel Gershkovich
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Advisory Committee
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outside member
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Rutgers University
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degree grantor
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School of Graduate Studies
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school
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Text
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theses
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2021
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2021-01
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English
Abstract
While drug development has traditionally focused on the general population, the number of individuals falling outside the ‘norm’ has continued to rise. For example, roughly 40% of the United States population is obese, and 15% is older than 65. Drug dosing is obscure in these patient populations, and a lack of knowledge may contribute to iatrogenesis. This concern is especially concerning with antibiotics due to emerging pathogen resistance and lack of drug development. Similarly, anticoagulant-related iatrogenesis remains one of the most common causes of hospital admission. This concern is heightened in individuals with extreme bodyweight and those of advanced age. Supporting evidence to substantiate concerns, identify mechanisms, and define solutions is urgently needed.

The thesis focused on using various approaches to evaluate drug exposure and response occurring with standard dosing strategies in special populations, namely individuals with obesity and advanced age. In the introductory Chapter (1), an overview of obesity and advanced age is provided. The epidemiology of these populations and expected pharmacokinetic and pharmacodynamics changes are summarized. Further, information related to critical medications (antibiotics and anticoagulants), and the importance of their dosing is provided. In Chapter 2, a prospective pharmacokinetic study was performed in patients undergoing sleeve gastrectomy surgery. In this study, both plasma and subcutaneous adipose tissue beta-lactam antibiotic exposure was measured after standard surgical prophylaxis dosing. These data were also used to develop a two and three-compartment model describing the disposition of cefoxitin and cefazolin in individuals with obesity. In Chapters 3 and 4, the pharmacokinetics and pharmacodynamics of select anticoagulants were evaluated. First, the pharmacodynamics of subcutaneous unfractionated heparin and enoxaparin was described in individuals with obesity undergoing bariatric surgery. In this study, both anti-factor Xa and measurements of thrombin generation and potential were captured and correlated to measures of body composition. Next, variability in dabigatran exposure in advanced age was investigated, suggesting that monitoring drug exposure may be necessary for this patient population.

In Chapter 5, the influence of body composition on intravenous immunoglobulin response was investigated in individuals with primary immunodeficiency. The relationship between body composition and immunoglobulin pharmacokinetic parameters was established. In Chapter 6, a modified Cockcroft-Gault equation was developed using data obtained from clinical patient data. The influence of obesity, age, and obesity on the accuracy of calculated glomerular filtration rate estimates was established. The modified equation improved the accuracy of estimation. Chapters 7 and 8 provide an overview of the thesis and our future directions, respectively, including an evaluation of the contributions of drug transporters and the gut microbiome on drug disposition. Collectively, the studies provided essential insights into the shortcomings of the current paradigm of drug dosing.

Obesity should be considered a special population by the Food and Drug Administration. Manufacturers should therefore be required to provide evidence that their dosing recommendations are adequate for extreme body weights. In terms of advanced age, this population is already considered a special population; however, a more rigorous evaluation of drugs is vital as the number of individuals in this group increases. Future studies are aimed at expanding on these data to provide dosing recommendations for special patient populations.
Subject (authority = local)
Topic
Obesity
Subject (authority = RUETD)
Topic
Pharmaceutical Science
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Rutgers University Electronic Theses and Dissertations
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ETD_11464
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application/pdf
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text/xml
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1 online resource (xv, 136 pages)
Note (type = degree)
Ph.D.
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Includes bibliographical references
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External ETD doctoral
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-t70a-b265
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The author owns the copyright to this work.
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Name
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Brunetti
GivenName
Luigi
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Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2021-01-07 19:55:10
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Name
Luigi Brunetti
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Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
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Copyright protected
Availability
Status
Open
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Permission or license
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