Multi-scale computational modeling towards efficacy in radiopharmaceutical therapies while minimizing side effects: Modeling of amino acid infusion

Amino acid infusion (AAI) is a technique used in radiopharmaceutical therapy (RPT) to reduce toxicity in kidney and increase clearance rate of radiopharmaceuticals from body. In this study our aim is to evaluate its effect in personalized RPT considering kidney and salivary glands as dose limiting organs using a multiscale modeling framework. We developed a Physiologically-Based Pharmacokinetic (PBPK) model consisting of 19 compartments, personalized it for four prostate cancer patients using data derived from gamma camera imaging. This model was used to investigate the influence of AAI on the absorbed dose to tumors and organs at risk. We then computed the maximum safe injected activity based on the PBPK model. To address the effects of interstitial fluid pressure (IFP) and tumor heterogeneity, we coupled the PBPK model with convection-diffusion-reaction (CDR) equations. To compare the effectiveness of our modeling approaches, we calculated absorbed doses to the tumors with and without AAI, using both the standalone PBPK model and the coupled PBPK-CDR model. Our findings revealed a relative error (RE) of 9.6% ± 2.2% (mean ± SD) in total tumor absorbed dose calculation between PBPK and CDR equations, attributable to the consideration of IFP. Moreover, AAI proved beneficial for RPT when the kidney was designated as the organ-at-risk. It enabled an increase in radiopharmaceutical injection from 12.3 ± 6.32 MBq (mean ± SD) to 15.45 ± 6.95 MBq (RE: 28.5% ± 15.7%), resulting in a corresponding increase in tumor absorbed dose from 67.8 ± 47.45 Gy to 72.43 ± 51.03 Gy (RE: 8.6% ± 5.4%), while maintaining critical kidney absorbed dose limits. However, this was not observed when the salivary gland was considered the dose-limiting organ. Although, AAI allowed for increased therapeutic injection ranging from 4.22 ± 2.23 MBq to 5.25 ± 3.14 MBq (RE: 19.2% ± 9.9%), it results in a minimal increase in tumor absorbed dose of 0.22 ± 0.04 (RE: 1.4% ± 1.3%). Statistical analysis using the Wilcoxon Signed-Rank Test revealed significant effects of AAI on administered activity and tumor absorbed dose (p-value = 0.007 < 0.05). Finally, a local sensitivity analysis was performed on selected radiation and tumor transportation parameters individually to evaluate their impact on the tumor absorbed dose. In conclusion, selection of organ-at-risk in personalized RPT is critical, as it determines the injected activity amount and the efficacy of delivery-enhancing techniques.