Nusrat J. Begum, G. Glatting, H. Wester, M. Eiber, A. Beer, P. Kletting
Scientific Reports, 2019
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 kon (0.1–0.01 L/nmol/min), dissociation rates koff (0.1–0.0001 min−1), internalization rates λint (0.01–0.0001 min−1) and ligand amounts (1–1000 nmol). For imaging the activity was normalized to volume and injected activity (68Ga-PSMA at 1 h). For therapy the absorbed dose was calculated for 7.3 ± 0.3 GBq 177Lu-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 kon = 0.1 L/nmol/min, koff = 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.
Cited by 9 publications.
Field of study: Chemistry