Physiologically Based RadioPharmacoKinetic (PBRPK) Modeling to Simulate and Analyze Radiopharmaceutical Therapies: Studies of Non-Linearities, Multi-Bolus Injections, and Albumin Binding

Abstract

Background: We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies. Results: To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the ”reaction graph” is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (i) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (ii) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (iii) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to a number of factors that PBRPK allows us to probe. Conclusions: Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.