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Background: There is an unmet need for prediction of treatment outcome or patient selection for [177Lu]Lu-PSMA therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Quantification of the tumor exposure–response relationship is pivotal for further treatment optimization. Therefore, a population pharmacokinetic (PK) model was developed for [177Lu]Lu-PSMA-I&T using SPECT/CT data and, subsequently, related to prostate-specific antigen (PSA) dynamics after therapy in patients with mCRPC using a pharmacokinetic/pharmacodynamic (PKPD) modelling approach. Methods: A population PK model was developed using quantitative SPECT/CT data (406 scans) of 76 patients who received multiple cycles [177Lu]Lu-PSMA-I&T (± 7.4 GBq with either two- or six-week interval). The PK model consisted of five compartments; central, salivary glands, kidneys, tumors and combined remaining tissues. Covariates (tumor volume, renal function and cycle number) were tested to explain inter-individual variability on uptake into organs and tumors. The final PK model was expanded with a PD compartment (sequential fitting approach) representing PSA dynamics during and after treatment. To explore the presence of a exposure–response relationship, individually estimated [177Lu]Lu-PSMA-I&T tumor concentrations were related to PSA changes over time. Results: The population PK model adequately described observed data in all compartments (based on visual inspection of goodness-of-fit plots) with adequate precision of parameters estimates (< 36.1% relative standard error (RSE)). A significant declining uptake in tumors (k14) during later cycles was identified (uptake decreased to 73%, 50% and 44% in cycle 2, 3 and 4–7, respectively, compared to cycle 1). Tumor growth (defined by PSA increase) was described with an exponential growth rate (0.000408 h−1 (14.2% RSE)). Therapy-induced PSA decrease was related to estimated tumor concentrations (MBq/L) using both a direct and delayed drug effect. The final model adequately captured individual PSA concentrations after treatment (based on goodness-of-fit plots). Simulation based on the final PKPD model showed no evident differences in response for the two different dosing regimens currently used. Conclusions: Our population PK model accurately described observed [177Lu]Lu-PSMA-I&T uptake in salivary glands, kidneys and tumors and revealed a clear declining tumor uptake over treatment cycles. The PKPD model adequately captured individual PSA observations and identified population response rates for the two dosing regimens. Hence, a PKPD modelling approach can guide prediction of treatment response and thus identify patients in whom radioligand therapy is likely to fail. [ABSTRACT FROM AUTHOR]

Background: Steps have been taken by pharmaceutical companies to obtain marketing authorisation of PSMA ligands in the European Union. Since December 2022, Locametz® (PSMA-11, gozetotide) is licensed as kit for manual radiolabelling with gallium-68 and commercially available since mid-2023. The Summary of Product Characteristic (SmPC) describes manual radiolabelling with a maximum activity after radiolabelling of 1369 MBq. We aimed for radiolabelling with a higher activity to increase production efficiency, and thus, automated radiolabelling is strongly preferred over manual radiolabelling to reduce radiation exposure to personnel. The aim of this study was to develop and validate a method for automated radiolabelling of the Locametz® kit using ~ 2000 MBq of gallium-68 eluate for radiolabelling. Results: Automated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit provided a product which complies to the Ph. Eur., had a shelf-life of 6 h at room temperature, and theoretically reduced radiation exposure 5.7 times. Radiolabelling with one and two generator(s) resulted in a radiochemical yield of 91–102% and 96–101% after preparation, respectively. The radiochemical purity ranged from 98.0 to 99.6% for radiolabelling with one generator and ranged from 98.4 to 99.3% for radiolabelling with two generators with similar stability. The activity of the final product was much higher when using two generators, 1961–2035 MBq compared to 740–1260 MBq, which leads to ~ 1.5 times more patient syringes available per preparation. Conclusion: Automated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit with higher gallium-68 activity than specified in the SmPC results in a product that is in compliance with the Ph. Eur. monograph and has a shelf-life of 6 h at room temperature. Radiolabelling with two generators proved possible and resulted in a product with similar quality but with much higher efficiency. [ABSTRACT FROM AUTHOR]

Background: Prediction of [177Lu]Lu-HA-DOTATATE kidney and tumor uptake based on diagnostic [68Ga]Ga-HA-DOTATATE imaging would be a crucial step for precision dosing of [177Lu]Lu-HA-DOTATATE. In this study, the population pharmacokinetic (PK) differences between [177Lu]Lu-HA-DOTATATE and [68Ga]Ga-HA-DOTATATE were assessed and subsequently [177Lu]Lu-HA-DOTATATE was predicted based on [68Ga]Ga-HA-DOTATATE imaging. Methods: A semi-physiological nonlinear mixed-effects model was developed for [68Ga]Ga-HA-DOTATATE and [177Lu]Lu-HA-DOTATATE, including six compartments (representing blood, spleen, kidney, tumor lesions, other somatostatin receptor expressing organs and a lumped rest compartment). Model parameters were fixed based on a previously developed physiologically based pharmacokinetic model for [68Ga]Ga-HA-DOTATATE. For [177Lu]Lu-HA-DOTATATE, PK parameters were based on literature values or estimated based on scan data (four time points post-injection) from nine patients. Finally, individual [177Lu]Lu-HA-DOTATATE uptake into tumors and kidneys was predicted based on individual [68Ga]Ga-HA-DOTATATE scan data using Bayesian estimates. Predictions were evaluated compared to observed data using a relative prediction error (RPE) for both area under the curve (AUC) and absorbed dose. Lastly, to assess the predictive value of diagnostic imaging to predict therapeutic exposure, individual prediction RPEs (using Bayesian estimation) were compared to those from population predictions (using the population model). Results: Population uptake rate parameters for spleen, kidney and tumors differed by a 0.29-fold (15% relative standard error (RSE)), 0.49-fold (15% RSE) and 1.43-fold (14% RSE), respectively, for [177Lu]Lu-HA-DOTATATE compared to [68Ga]Ga-HA-DOTATATE. Model predictions adequately described observed data in kidney and tumors for both peptides (based on visual inspection of goodness-of-fit plots). Individual predictions of tumor uptake were better (RPE AUC –40 to 28%) compared to kidney predictions (RPE AUC –53 to 41%). Absorbed dose predictions were less predictive for both tumor and kidneys (RPE tumor and kidney –51 to 44% and –58 to 82%, respectively). For most patients, [177Lu]Lu-HA-DOTATATE tumor accumulation predictions based on individual PK parameters estimated from diagnostic imaging outperformed predictions based on population parameters. Conclusion: Our semi-physiological PK model indicated clear differences in PK parameters for [68Ga]Ga-HA-DOTATATE and [177Lu]Lu-HA-DOTATATE. Diagnostic images provided additional information to individually predict [177Lu]Lu-HA-DOTATATE tumor uptake compared to using a population approach. In addition, individual predictions indicated that many aspects, apart from PK differences, play a part in predicting [177Lu]Lu-HA-DOTATATE distribution. [ABSTRACT FROM AUTHOR]

Studies to evaluate and optimize [177Lu]Lu‐PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [177Lu]Lu‐PSMA‐617 in patients with low volume metastatic prostate cancer. Simulations were performed to identify the effect of dose adjustments on absorbed doses in salivary glands and tumors. A six‐compartment population PK model was developed, consisting of blood, salivary gland, kidneys, liver, tumor, and a lumped compartment representing other tissue (compartment 1–6, respectively), based on data from 10 patients who received [177Lu]Lu‐PSMA‐617 (2 cycles, ~ 3 and ~ 6 GBq). Data consisted of radioactivity levels (decay corrected) in blood and tissues (9 blood samples and 5 single photon emission computed tomography/computed tomography scans). Observations in all compartments were adequately captured by individual model predictions. Uptake into salivary glands was saturable with an estimated maximum binding capacity (Bmax) of 40.4 MBq (relative standard error 12.3%) with interindividual variability (IIV) of 59.3% (percent coefficient of variation [CV%]). IIV on other PK parameters was relatively minor. Tumor volume was included as a structural effect on the tumor uptake rate constant (k15), where a two‐fold increase in tumor volume resulted in a 1.63‐fold increase in k15. In addition, interoccasion variability on k15 improved the model fit (43.5% [CV%]). Simulations showed a reduced absorbed dose per unit administered activity for salivary glands after increasing radioactivity dosing from 3 to 6 GBq (0.685 Gy/GBq vs. 0.421 Gy/GBq, respectively). All in all, population PK modeling could help to improve future radioligand therapy research. [ABSTRACT FROM AUTHOR]

Background: Folate intake might reduce [68Ga]Ga-PSMA-11 uptake in tissues due to a competitive binding to the PSMA receptor. For diagnostic imaging, this could impact decision making, while during radioligand therapy this could affect treatment efficacy. The relationship between folate dose, timing of dosing and tumor and organ uptake is not well established. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the effect of folates on [68Ga]Ga-PSMA-11 PET/CT uptake in salivary glands, kidneys and tumors. Methods: A PBPK model was developed for [68Ga]Ga-PSMA-11 and folates (folic acid and its metabolite 5-MTHF), with compartments added that represent salivary glands and tumor. Reactions describing receptor binding, internalization and intracellular degradation were included. Model evaluation for [68Ga]Ga-PSMA-11 was performed by using patient scan data from two different studies (static and dynamic), while for folates data from the literature were used for evaluation. Simulations were performed to assess the effect of different folate doses (150 µg, 400 µg, 5 mg and 10 mg) on accumulation in salivary glands, kidney and tumor, also for patients with different tumor volumes (10, 100, 500 and 1000 mL). Results: Final model evaluation showed that predictions adequately described data for both [68Ga]Ga-PSMA-11 and folates. Predictions of a 5-MTFH dose of 150 µg and folic acid dose of 400 µg (in case of administration at the same time as [68Ga]Ga-PSMA-11 (t = 0)) showed no clinically relevant effect on salivary glands and kidney uptake. However, the effect of a decrease in salivary glands and kidney uptake was determined to be clinically relevant for doses of 5 mg (34% decrease for salivary glands and 32% decrease for kidney) and 10 mg (36% decrease for salivary glands and 34% decrease for kidney). Predictions showed that tumor uptake was not relevantly affected by the co-administration of folate for all different folate doses (range 150 µg–10 mg). Lastly, different tumor volumes did not impact the folate effect on [68Ga]Ga-PSMA-11 biodistribution. Conclusion: Using a PBPK model approach, high doses of folate (5 and 10 mg) were predicted to show a decrease of [68Ga]Ga-PSMA-11 salivary glands and kidney uptake, while intake by means of folate containing food or vitamin supplements showed no relevant effects. In addition, tumor uptake was not affected by folate administration in the simulated dose ranges (150 µg–10 mg). Differences in tumor volume are not expected to impact folate effects on [68Ga]Ga-PSMA-11 organ uptake. [ABSTRACT FROM AUTHOR]

Purpose: According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4–6 weeks prior to peptide receptor radionuclide therapy (PRRT) to prevent somatostatin receptor saturation. The aim of this study was to determine the effect of continued use of long-acting SSAs during PRRT on the uptake of [177Lu]Lu-HA-DOTATATE on SPECT/CT. Methods: Consecutive patients with neuroendocrine tumours who were treated with PRRT receiving 7.4 GBq of [177Lu]Lu-HA-DOTATATE were included. Patients were divided into 3 groups: (1) control (LA-SSA stopped > 6 weeks prior to PRRT), or continued treatment with (2) long-acting octreotide < 6 weeks prior to PRRT, or (3) long-acting lanreotide < 6 weeks prior to PRRT. The uptake of [177Lu]Lu-HA-DOTATATE was quantified in healthy tissues (spleen, liver, kidneys, bone marrow) and tumour lesions on SPECT/CT performed 24 h after PRRT. A Mann–Whitney U test was used to determine differences in uptake between the long-acting octreotide and long-acting lanreotide groups compared to the control group. Results: Forty-two patients with 135 cycles of PRRT were included: 28 with lanreotide, 50 with octreotide, and 57 cycles without LA-SSAs. Uptake of [177Lu]Lu-HA-DOTATATE was significantly decreased in liver parenchyma in patients with lanreotide (p < 0.001) and in the spleen in patients with either octreotide or lanreotide (both p < 0.001). No differences were observed for uptake in kidneys, bone marrow, and blood pool. Uptake of [177Lu]Lu-HA-DOTATATE in tumours was the same in patients with lanreotide compared to the control (p = 0.862) and in patients with octreotide compared to the control (p = 0.201), independent of tumour location. Conclusion: Long-acting octreotide and lanreotide do not interfere with the uptake of [177Lu]Lu-HA-DOTATATE in tumour lesions 24 h post-injection. Uptake in healthy liver parenchyma significantly decreases after lanreotide administration prior to PRRT, while uptake in healthy spleen tissue significantly decreases with both octreotide and lanreotide administration. [ABSTRACT FROM AUTHOR]

Background: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various 68Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed. Methods: A PBPK model was developed for [68Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect. Results: Data of 39 and 59 patients receiving [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL. Conclusion: The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as [177Lu]Lu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control. Results: Downscaled conditions (74 MBq/μg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%. Conclusion: This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed [177Lu]Lu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality. [ABSTRACT FROM AUTHOR]

Background: [177Lu]Lu-PSMA is used for the treatment of metastatic castration-resistant prostate cancer. For in-house productions, quality control methods are essential for ensuring product quality, and thus patient safety. During HPLC method development for quality control of [177Lu]Lu-PSMA-I&T, we noticed an unpredictable variability in peak area and height with replicate measurements. After a run, irremovable radioactivity was measured over the whole the length of the HPLC column, with slightly higher activity at the beginning and end of the column. The uniform distribution suggests that [177Lu]Lu-PSMA-I&T interacts with the column. As a result of the interaction, incomplete and variable recovery of injected activity was observed leading to the variability in peak area and height. Therefore the aim of this study was to (1) investigate the effect of sample composition on the interaction of [177Lu]Lu-PSMA-I&T to the HPLC column (measured as recovery, peak area, and peak height), and (2) to compare this with same concentrations of the well-known [177Lu]Lu-PSMA-617. Results: Sample composition significantly affects recovery of [177Lu]Lu-PSMA-I&T, leading to a change in peak area and height. Recovery was 24% when diluted with 0.1 mM octreotide, 38% with water, and increased to 95% when diluted with 0.7 mM unlabeled PSMA-I&T. Peak area and height decreased to 26% and 17% when diluted in octreotide and to 41% and 29% when diluted in water, compared to a dilution in PSMA-I&T. Further experiments showed that recovery (and consequently peak area and peak height) reached a plateau of > 99% at concentrations of 0.27 mM and higher. [177Lu]Lu-PSMA-617 also interacts with the HPLC column, leading to lower, but less variable, recovery (9%). The low recovery of [177Lu]Lu-PSMA-617 could not be prevented with addition of unlabeled PSMA-617. Conclusion: [177Lu]Lu-PSMA-I&T can undergo an irreversible binding with an HPLC column resulting in a decreased recovery. The recovery is can be highly dependent on sample composition. The addition of a surplus of unlabeled PSMA-I&T leads to an accurate analysis of [177Lu]Lu-PSMA-I&T. [ABSTRACT FROM AUTHOR]