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Dissertation
Characterizing pharmacokinetic-pharmacodynamic relationships of VSV-GP
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2024
DOI:
https://doi.org/10.17918/00010480
Abstract
Oncolytic viruses (OVs) have the potential to destroy tumors, drive adaptive antitumor immune responses, and break barriers of immune tolerance to other immunotherapies. The premise of using live replicating viruses for cancer therapy has culminated in numerous clinical trials and an FDA-approved product. However, OVs pose unique challenges for pharmacology-based drug development compared to traditional drugs. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments - the study of drug fate and drug effect, respectively - are complicated by the viruses' ability to replicate and their multifaceted mechanisms of action. Consequently, many key PK and PD characteristics of OVs remain abstruse, such as the impacts of replication on exposure, dose proportionality, and exposure-response relationships. This thesis provides a baseline characterization of PK-PD relationships for a model OV, VSV-GP, after systemic administration in mice. We first developed methods to quantify and differentiate the exposure contribution from the input virus and its replication using an inactivated tool virus. This provided a valuable PK quantification of viral replication that was applied throughout subsequent studies. Biodistribution (BD) was also assessed which revealed tissue-specific differences in distribution and replication permissivity driven by tissue resident macrophages. Based on this finding, we then conducted experiments to further evaluate the impacts of innate immune responses on VSV-GP PK/BD, which highlighted the role of the type-I interferon response as a determinant of PK and BD. Finally, we conducted a thorough evaluation of the dose-exposure-response relationships for VSV-GP in tumor-bearing and tumor-free mice by modulating dose level and infusion rate and measuring several PK and PD markers. These experiments quantified the impact of tumoral replication on systemic exposure and revealed the linear nature of the PK/BD profile, which was dose-proportional but not impacted by infusion rate. Overall, VSV-GP exhibited dose dependent PK-PD relationships which were driven by total exposure, replication, and innate immune responses. Altogether, these efforts refined the PK/BD/PD profile for a replicating OV, elucidated PK-PD relationships, and developed a framework that can be applied to other viruses. These advances may be helpful to inform safety and efficacy considerations, develop PK-PD models, and optimize dose regimens to help realize the full potential of OVs.
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Details
- Title
- Characterizing pharmacokinetic-pharmacodynamic relationships of VSV-GP
- Creators
- Richard Michael Dambra
- Contributors
- Joseph Ashour (Advisor)Lin Han (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xix, 266 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991021890311404721