Radiobiological-guided radiopharmaceutical therapy: Radiopharmacokinetic parameter optimization using PBPK modeling

We developed a whole-body physiologically based pharmacokinetic (PBPK) model to simulate and predict the distribution and uptake of PSMA-targeted radiopharmaceuticals in the tumor and normal tissues. Using this model, we evaluated different theoretical ranges of pharmacokinetic parameters, including association rate, serum flow density, half-life, internalization rate, ligand amount, surface permeability, receptor density, release rate, and serum protein binding rate. The resulting time-activity curves were used to calculate the biologically effective dose (BED) for the tumor, salivary gland, and kidney. We performed sensitivity analysis and observed that changing the parameters had varied effects on the BED values. We found that tumor volume, followed by ligand amount and tumor receptor density, are the most important factors in BED. Furthermore, radiopharmaceuticals therapy (RPT) using long half-life radionuclides will increase the BED in tumors and organs-at-risk (OARs). Similarly, changes in the pharmacokinetic parameters had varying impacts on the figure-of-merit BED (fBED), which we calculated as the ratio of the BEDs of OARs to tumor. Our results showed that changes the tumor receptor density had the most significant impact on fBED values, up to 30-40-fold, while changes in the association rate had the least impact limited to few percents. These findings highlight the importance of considering the effects of pharmacokinetic parameters when evaluating the efficacy of radiopharmaceuticals in targeted radiation therapy.