The effect of ligand amount, affinity and internalization on PSMA-targeted imaging and therapy: A simulation study...

Area of Science:

• Nuclear Medicine
• Radiopharmaceutical Chemistry
• Pharmacokinetics

Background:

• Prostate-specific membrane antigen (PSMA)-specific ligands are crucial for diagnosing and treating prostate cancer.
• Optimizing ligand properties is essential for maximizing therapeutic efficacy and minimizing off-target toxicity.
• Physiologically-based pharmacokinetic (PBPK) modeling offers a powerful tool for predicting ligand behavior in vivo.

Purpose of the Study:

• To investigate the impact of PSMA-specific ligand characteristics (amount, affinity, internalization) on PET/CT imaging and radionuclide therapy.
• To determine optimal parameters for enhancing tumor uptake and reducing absorbed radiation doses.
• To utilize PBPK modeling for in silico analysis of ligand behavior in virtual patients.

Main Methods:

• Implementation of a PBPK model for PSMA-specific ligands.
• Simulation of thirteen virtual patients with metastatic castration-resistant prostate cancer.
• Analysis of varying association rates (k_on), dissociation rates (k_off), internalization rates (λ_int), and ligand amounts.

Main Results:

• Ligand properties had a greater effect on therapy outcomes than on imaging.
• Optimal imaging conditions involved specific k_on and k_off values with typical ligand amounts.
• For therapy, higher internalization rates required larger ligand amounts for favorable tumor-to-kidney ratios, and higher affinity necessitated careful ligand amount selection.

Conclusions:

• PBPK modeling provides valuable insights into the pharmacokinetics of PSMA-specific ligands.
• Ligand affinity and internalization rates critically influence therapeutic outcomes and dose optimization.
• Further in silico and in vivo studies are needed to validate these findings and refine treatment protocols.