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


ABSTRACT: 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 ?int (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.

SUBMITTER: Begum NJ 

PROVIDER: S-EPMC6934468 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Begum Nusrat J NJ   Glatting Gerhard G   Wester Hans-Jürgen HJ   Eiber Matthias M   Beer Ambros J AJ   Kletting Peter P  

Scientific reports 20191227 1


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 asso  ...[more]

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