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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]