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Fele-Paranj, Ali

University of British Columbia

In this thesis, we developed a computational framework using physiologically based pharmacokinetic (PBPK) models to study radiopharmaceutical kinetics in the body. To handle the complexity of PBPK models (over 100 differential equations), a scalable modeling notation called the "reaction graph" is introduced. Implemented in Matlab's Simbiology module and shared in the systems biology markup language (SBML) format, this notation enables easy model reproduction. Referred to as the physiologically based radiopharmacokinetic model (PBRPK), it is fine-tuned specifically for radiopharmaceuticals. Using the PBRPK model and literature-based parameters, we addressed three key questions in radiopharmaceutical therapy. First, we systematically studied the interaction between hot and cold species and its impact on absorbed dose in tumors and organs at risk (OARs) and we found out that tumor receptor density and volume influence the degree of competition and the average absorbed dose in tumors and OARs in a way that lower receptor density (or lower tumor volume) leads to more dominant competition between hot and cold species that is the absorbed dose by tumor highly depends on the number of cold ligands injected to the patient. Next, the effect of injecting radiopharmaceuticals in smaller portions and with specific timing is investigated. We found that bolus injection leads to non-efficient receptor binding and sub-optimal delivered doses to the tumor and organs at risk. However, we found that injecting in several smaller portions leads to a higher absorbed dose by tumors and organs at risk. So multi-bolus injection can be thought of as a tool that increases the delivered dose to the tumor and OAR without any differential effect (delivering mode dose to the tumor and sparing OAR) Finally, the PBRPK model is used to simulate the impact of albumin affinity on radiopharmaceutical kinetics. Varying albumin affinity of the radiopharmaceuticals reveals changes in blood residence time, with lower dissociation rates resulting in longer residence times. Generally, lower dissociation rates increase tumor absorbed dose and decrease OAR dose, which makes the albumin binding a potential tool to achieve differential enhancement in targeting tumors and sparing OAR.

Text

2024-01-15

Attribution-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87272

Biomedical Engineering

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nd/4.0/