The Impact of Peptide Amount on Tumor Uptake to Assess PSMA Receptor Saturation on 68Ga-PSMA-11 PET/CT in Patients with Primary Prostate Cancer.

68Ga-labeled prostate-specific membrane antigen (PSMA) is often produced on-site, where usually a fixed amount of peptide is conjugated to the generator eluate. However, fluctuations in specific activity might influence tracer distribution and tumor accumulation. Therefore, our aim was to investigate the potential effect of varying the administered peptide amount on 68Ga-PSMA-11 uptake in tumors using PET/CT in patients with primary prostate cancer (PCa). Additionally, the impact of tumor volume on this potential effect and on accumulation in reference organs was assessed. Methods: The imaging data of 362 men with primary PCa who underwent 68Ga-PSMA-11 PET/CT were retrospectively included. Scans were quantified for normal tissue and primary tumors. Patients were divided into 3 groups based on their tumor volume. Correlation and multivariable linear regression analyses were performed. Results: The median index lesion volume was 9.50 cm3 (range, 0.064-174 cm3). Groups were based on quartiles of prostatic lesion volume: ≤4.11 cm3 (group 1), 4.11-20.6 cm3 (group 2), and ≥20.6 cm3 (group 3). No correlation was found between administered peptide amount and tumor uptake (SUVmean or SUVpeak) for any group, except for a significant correlation for SUVmean in the first group (P = 0.008). Linear regression analysis supported these findings. Conclusion: The amount of administered peptide had no evident effect on 68Ga-PSMA-11 uptake in tumors, except for a significant positive correlation between administered peptide amount and tumor SUVmean for group 1. The findings imply that no receptor saturation occurs in men with primary PCa at peptide levels of about 2.5 µg.

Somatostatin receptor saturation after administration of high peptide amounts of [177Lu]Lu-HA-DOTATATE: when enough is enough.

BACKGROUND: Receptor saturation during peptide receptor radionuclide therapy (PRRT) could result in altered [177Lu]Lu-HA-DOTATATE uptake in tumors and organs. Therefore, receptor expression status and effects of different (unlabeled) administered peptide amounts during PRRT need to be evaluated. The aim of this study was to assess potential receptor saturation during PRRT by comparing organ and tumor uptake after administration of [177Lu]Lu-HA-DOTATATE with low, standard and high administered peptide amounts in patients with advanced metastatic neuroendocrine tumors (NETs). METHODS: Data of NET patients that received 7.4 GBq 177-Lutetium labeled to a low or high amount of HA-DOTATATE were retrospectively included. From included patients other PRRT cycles, containing standard administered peptide amounts, were included for intra-patient comparison. Uptake quantification was performed for spleen, liver, kidney, bone marrow, blood pool and tumor lesions on post-treatment SPECT/CT scans. A paired Wilcoxon signed-rank test was performed to determine uptake differences between two adjacent cycles for each patient. RESULTS: Thirteen patients received [177Lu]Lu-HA-DOTATATE with a high administered peptide amount (mean 346 µg vs 178 µg standard peptide amount). Low peptide amounts were administered to fifteen patients (mean 109 µg vs 202 µg standard peptide amount). High administered peptide amount resulted in significantly lower [177Lu]Lu-HA-DOTATATE uptake in the spleen (p = 0.00012), kidney (p = 0.013) and tumor lesions (p < 0.0001) versus standard peptide amounts. For low administered peptide amount, uptake was increased in the spleen (p = 0.015), while tumor uptake was significantly reduced (p = 0.015) compared to uptake after administration of standard peptide amounts. CONCLUSIONS: These findings confirmed a peptide amount-dependent organ and tumor accumulation for [177Lu]Lu-HA-DOTATATE, with receptor saturation in spleen for high and standard peptide amounts, while tumor and kidney receptor saturation occur only with high administered peptide amounts. A high peptide amount (~ 350 µg) is not recommended for standard-dose PRRT and standard amounts (~ 200 µg) seem more suitable to achieve optimal tumor accumulation with limited organ uptake.

A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors.

BACKGROUND: Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). METHODS: Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30-60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. RESULTS: 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05-16.9 µg) labeled with 92.7 MBq (range 43.4-129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. CONCLUSIONS: To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.

Optimized Peptide Amount and Activity for 9°Y-Labeled DOTATATE Therapy.

UNLABELLED: In peptide receptor radionuclide therapy with (90)Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity that can be safely administered in many patients. A higher tumor-to-kidney absorbed dose ratio might be achieved by optimizing the amount of injected peptide and activity, as recent studies have shown different degrees of receptor saturation for normal tissue and tumor. The aim of this work was to develop and implement a modeling method for treatment planning to determine the optimal combination of peptide amount and pertaining therapeutic activity for each patient. METHODS: A whole-body physiologically based pharmacokinetic (PBPK) model was developed. General physiologic parameters were taken from the literature. Individual model parameters were fitted to a series (n= 12) of planar γ-camera and serum measurements ((111)In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, we determined the tumor, liver, spleen, and red marrow biologically effective doses (BEDs) for a maximal kidney BED (20 Gy2.5) for different peptide amounts and activities. The optimal combination of peptide amount and activity for maximal tumor BED, considering the additional constraint of a red marrow BED less than 1 Gy15, was individually quantified. RESULTS: The PBPK model describes the biokinetic data well considering the criteria of visual inspection, the coefficients of determination, the relative standard errors (<50%), and the correlation of the parameters (<0.8). All fitted parameters were in a physiologically reasonable range but varied considerably between patients, especially tumor perfusion (meningioma, 0.1-1 mL·g(-1)·min(-1), and NETs, 0.02-1 mL·g(-1)·min(-1)) and receptor density (meningioma, 5-34 nmol·L(-1), and NETs, 7-35 nmol·L(-1)). Using the proposed method, we identified the optimal amount and pertaining activity to be 76 ± 46 nmol (118 ± 71 µg) and 4.2 ± 1.8 GBq for meningioma and 87 ± 50 nmol (135 ± 78 µg) and 5.1 ± 2.8 GBq for NET patients. CONCLUSION: The presented work suggests that to achieve higher efficacy and safety for (90)Y-DOATATE therapy, both the administered amount of peptide and the activity should be optimized in treatment planning using the proposed method. This approach could also be adapted for therapy with other peptides.