Abstract
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.
Highlights
Molecular radiotherapy using 177Lu-labeled prostate specific membrane antigen (PSMA) specific peptides is a promising novel approach for the treatment of metastatic prostate cancer [1,2,3]
PSMA is expressed with relevant density in the salivary glands [4] and kidneys [5], where specific binding in combination with unspecific uptake can lead to considerable absorbed doses [6, 7]
Physiologically based pharmacokinetic (PBPK) modeling, that allows simulating the pharmacokinetics for different peptide amounts using general physiological and patient individual parameters estimated based on imaging data, represents a suitable method [9, 10]
Summary
Molecular radiotherapy using 177Lu-labeled PSMA specific peptides is a promising novel approach for the treatment of metastatic prostate cancer [1,2,3]. To increase the tumor-to-kidney absorbed dose or biologically effective dose (BED) ratio, amino acids are administered to block unspecific uptake at some institutions analogous to peptide receptor radionuclide therapy (PRRT), evidence on the relevance of this approach for PSMA-targeted radionuclide therapy is still missing. A high tumor-tokidney ratio for binding site density together with a low ratio for tumor-to-kidney perfusion resulted in a strong influence of the peptide amount on the BED ratio. These results were in agreement with other studies for similar substances [12, 13]. We conjectured an even stronger effect for PSMA targeting ligands, as high tumor binding site densities compared to normal tissue have been reported in vitro [14,15,16]
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