Model-Informed Radiopharmaceutical Therapy Optimization: A Study on the Impact of PBPK Model Parameters on Physical, Biological, and Statistical Measures in 177Lu-PSMA Therapy

<b><i>Purpose:</i></b> To investigate the impact of physiologically based pharmacokinetic (PBPK) parameters on physical, biological, and statistical measures in lutetium-177-labeled radiopharmaceutical therapies (RPTs) targeting the prostate-specific membrane antigen (PSMA). <b><i>Methods:</i></b> Using a clinically validated PBPK model, realistic time-activity curves (TACs) for tumors, salivary glands, and kidneys were generated based on various model parameters. These TACs were used to calculate the area-under-the-TAC (AUC), dose, biologically effective dose (BED), and figure-of-merit BED (fBED). The effects of these parameters on radiobiological, pharmacokinetic, time, and statistical features were assessed. <b><i>Results:</i></b> Manipulating PBPK parameters significantly influenced AUC, dose, BED, and fBED outcomes across four different BED models. Higher association rates increased AUC, dose, and BED values for tumors, with minimal impact on non-target organs. Increased internalization rates reduced AUC and dose for tumors and kidneys. Higher serum protein-binding rates decreased AUC and dose for all tissues. Elevated tumor receptor density and ligand amounts enhanced uptake and effectiveness in tumors. Larger tumor volumes required dosimetry adjustments to maintain efficacy. Setting the tumor release rate to zero intensified the impact of association and internalization rates, enhancing tumor targeting while minimizing the effects on salivary glands and kidneys. <b><i>Conclusions:</i></b> Optimizing PBPK parameters can enhance the efficacy of lutetium-177-labeled RPTs targeting PSMA, providing insights for personalized and effective treatment regimens to minimize toxicity and improve therapeutic outcomes.