The effect of ligand amount, affinity and internalization on PSMA-targeted imaging and therapy: A simulation study using a PBPK model

The aim of this work was to investigate the effect of ligand amount, affinity and internalization of prostate-specific membrane antigen (PSMA)-specific ligands on the activity concentrations for PET/CT imaging and on the absorbed doses for therapy. A physiologically-based pharmacokinetic (PBPK) model for PSMA-specific ligands was implemented. Thirteen virtual patients with metastatic castration-resistant prostate cancer were analysed. Simulations were performed for different combinations of association rates k(on) (0.1–0.01 L/nmol/min), dissociation rates k(off) (0.1–0.0001 min(−1)), internalization rates λ(int) (0.01–0.0001 min(−1)) and ligand amounts (1–1000 nmol). For imaging the activity was normalized to volume and injected activity ((68)Ga-PSMA at 1 h). For therapy the absorbed dose was calculated for 7.3 ± 0.3 GBq (177)Lu-PSMA. The effect of the investigated parameters on therapy were larger compared to imaging. For imaging, the combination of properties leading to the highest tumour uptake was k(on) = 0.1 L/nmol/min, k(off) = 0.01 min(−1) for typical ligand amounts (1–10 nmol). For therapy, the higher the internalization rate, the larger was the required ligand amount for optimal tumour-to-kidney ratios. The higher the affinity, the more important was the choice of the optimal ligand amount. PBPK modelling provides insight into the pharmacokinetics of PSMA-specific ligands. Further in silico and in vivo studies are required to verify the influence of the analysed parameters.