Characterizing Pharmacokinetic-Pharmacodynamic Relationships of VSV-GP

Friday, May 31, 2024

12:00 PM-2:00 PM

BIOMED PhD Thesis Defense

Title:
Characterizing Pharmacokinetic-Pharmacodynamic Relationships of VSV-GP

Speaker:
Richard M. Dambra, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Scientist
Boehringer Ingelheim

Advisors:
Joseph Ashour, PhD
Senior Principal Scientist
Boehringer Ingelheim

Lin Han, PhD
Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Oncolytic viruses (OVs) are a re-emerging treatment modality that have the potential to destroy tumors, drive adaptive antitumor immune responses, and break barriers of immune tolerance to other immunotherapies. This premise of using replicating viruses as cancer therapeutics has led to 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, key PK-PD characteristics for OVs remain abstruse.

This thesis provides an in-depth characterization of the PK-PD relationships for a model OV, VSV-GP, after systemic administration in mice. First, methods were developed to quantify and differentiate the exposure contribution from the input virus and its replication using an inactivated tool virus, which provided a valuable PK characterization of viral replication that was applied throughout subsequent studies. Biodistribution (BD) was also assessed to quantify disposition and replication throughout tissues, revealing tissue-specific differences in distribution and permissivity to viral replication which was dependent on tissue resident macrophages. Based on this finding, experiments were then conducted to further evaluate the impacts of innate immune responses on VSV-GP PK/BD. These experiments highlighted the role of the type-I interferon response as a determinant of PK and BD. Finally, dose-exposure-response relationships for VSV-GP were thoroughly evaluated in tumor-bearing mice by modulating dose level and infusion rate and measuring several PK and PD markers. In these experiments, VSV-GP exhibited dose-proportional PK/BD which was impacted by the presence of a permissive tumor, but not by infusion rate. Furthermore, VSV-GP exhibited dose dependent PK-PD relationships which were predominantly driven by the overall systemic exposure.

Altogether, these efforts refined the PK/BD/PD profile for a replicating OV, elucidated PK-PD relationships, and developed a framework which could be applied to other replicating vectors. These advances may be helpful to inform safety and efficacy considerations, develop predictive PK-PD models, and optimize dose regimens to help realize the full potential of oncolytic virotherapy.

Contact Information

Natalia Broz
njb33@drexel.edu