Central Nervous System Delivery and Pharmacokinetics of Novel Therapeutics: Implications for Combinations of Small Molecules and Antibody-drug Conjugates
2022-06
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Central Nervous System Delivery and Pharmacokinetics of Novel Therapeutics: Implications for Combinations of Small Molecules and Antibody-drug Conjugates
Authors
Published Date
2022-06
Publisher
Type
Thesis or Dissertation
Abstract
The central nervous system (CNS) barriers, in particular the blood-brain barrier (BBB), play a critical role in the delivery, safety, and efficacy of drugs. The BBB prevents the distribution of a wide variety of molecules into brain, either due to the limited paracellular transport of large and hydrophilic molecules, or the active efflux of many small, lipophilic compounds with appreciable membrane permeability. Limited brain penetration of drugs can be an asset to the development of molecules for which dose-limiting toxicities are mediated within the CNS. This is of particular interest in the case of opioids, as their CNS side effects can be fatal. On the other hand, the limited delivery of drugs to the brain has been one of the greatest barriers to the development of novel therapies to treat diseases of the CNS, including brain tumors like glioblastoma (GBM). The objective of this dissertation was to assess how the BBB impacts the distribution of drugs in both of the aforementioned cases. In this dissertation, we utilized preclinical pharmacokinetic studies in wild-type and transgenic mice to characterize the CNS disposition of both opioids and antibody-drug conjugates (ADCs) following multiple routes of administration. This work shows that efflux by P-glycoprotein limits the CNS distribution of two opioid agonists with synergistic activity, loperamide and oxymorphindole, and indicates that their synergy is mediated in the peripheral nervous system. The subsequent work on the ADC, ABBV-221, shows that systemic administration of ADCs is unlikely to result in efficacious drug delivery to GBM tumors, but that administration by convection-enhanced delivery significantly enhances the exposure in brain. Together, these studies provide opposing perspectives on how CNS penetration can affect the safety and efficacy of novel therapeutics.
Description
University of Minnesota Ph.D. dissertation. June 2022. Major: Pharmaceutics. Advisor: William Elmquist. 1 computer file (PDF); xiv, 189 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Griffith, Jessica. (2022). Central Nervous System Delivery and Pharmacokinetics of Novel Therapeutics: Implications for Combinations of Small Molecules and Antibody-drug Conjugates. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241589.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.