SEARCHOTHERoncology, preclinical research

other·oncology, preclinical research, biomedical research, research methods·PMC10524596

A physiologically based pharmacokinetic model for V937 oncolytic virus in mice

Frontiers in Pharmacology · 4 authors, 4 centres

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TL;DR

The model described V937 distribution based on organ blood flows and volumes, using a non-linear mixed-effects approach.

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The model described V937 distribution based on organ blood flows and volumes, using a non-linear mixed-effects approach. The model incorporated a saturable uptake process for the muscle and heart, where peak levels occurred on day 3.

STUDY TYPE

other

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10524596

A physiologically based pharmacokinetic model for V937 oncolytic virus in mice

Frontiers in Pharmacology

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ABSTRACT

Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Results: Viral levels showed a drop from 10 8 to 10 5 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration. Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.

CITATION EXPORT

Sara Peribañez-Dominguez, Zinnia P. Parra-Guillen, Tomoko Freshwater et al.. A physiologically based pharmacokinetic model for V937 oncolytic virus in mice. Frontiers in Pharmacology. (2023). https://doi.org/10.3389/fphar.2023.1211452

AUTHORS

4 · 4 CENTRES

Sara Peribañez-Dominguez, Zinnia P. Parra-Guillen, Tomoko Freshwater, Iñaki F. Troconiz

1 Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
2 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
3 Quantitative Pharmacology and Pharmacometrics Immune/Oncology (QP2-I/O) Merck & Co., Inc., Rahway, NJ, United States
4 Institute of Data Science and Artificial Intelligence (DATAI), University of Navarra, Pamplona, Spain