Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.
In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.
Department of Nuclear Medicine, Ulm University, Ulm, Germany.
Peter
http://orcid.org/0000-0003-3654-3667
P
Kletting
THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
Christiane
C
Schuchardt
THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
Harshad R
HR
Kulkarni
THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
Mostafa
M
Shahinfar
THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
Aviral
A
Singh
Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Gerhard
G
Glatting
THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
Richard P
RP
Baum
Department of Nuclear Medicine, Ulm University, Ulm, Germany.
Ambros J
AJ
Beer
D000368:Aged; D000954:Antigens, Surface / Q000737:chemistry / Q000627:therapeutic use*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008187:Lutetium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012189:Retrospective Studies; D012469:Salivary Glands / Q000378:metabolism
D000954:Antigens, Surface; D008024:Ligands; D010455:Peptides; D011868:Radioisotopes; D008187:Lutetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II