Aim: To simulate the effect of PSMA positive total tumor volume (TTV) on the tumor and organs at risk (OARs) biologically effective doses (BEDs) in patients with metastatic castration resistant prostate cancer (mCRPC) in ¹⁷⁷Lu-PSMA radioligand therapy. Methods: A physiologically-based pharmacokinetic model was fitted to data of 13 patients treated with ¹⁷⁷Lu-PSMA I&T. The tumor, kidneys and salivary glands BEDs were simulated for TTVs of 0.1-10 l. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. Results: Increasing the TTV from 0.3 to 3 l, the simulated BEDs for tumor, kidneys, parotid and submandibular glands decreased from (22±15) Gy1.49 to (11.0±6.0) Gy1.49, (6.5±2.3) Gy2.5 to (3.7±1.4) Gy2.5, (10.9±2.7) Gy4.5 to (6.4±1.9) Gy4.5, and (11.0±2.7) Gy4.5 to (6.3±1.9) Gy4.5, respectively. The BED for the red marrow increased from (0.17±0.05) Gy15 to (0.32±0.11) Gy15. For patients with TTV > 0.3 l, the optimal amounts of peptide and activity were (273±136) nmol labeled with (10.4±4.4) GBq. Conclusion: This simulation study suggests that in patients with large PSMA positive tumor volumes higher activity and peptide amounts could be safely administered to maximize tumor BEDs without exceeding the tolerable BED for the OARs.

The aim of this work was to develop a theranostic method that allows predicting PSMA-positive tumor volume after radioligand therapy (RLT) based on a pre-therapeutic PET/CT measurement and physiologically based pharmacokinetic/dynamic (PBPK/PD) modeling at the example of RLT using ¹⁷⁷Lu-labeled PSMA for imaging and therapy (PSMA I&T). Methods: A recently developed PBPK model for ¹⁷⁷Lu PSMA I&T RLT was extended to account for tumor (exponential) growth and reduction due to irradiation (linear quadratic model). Data of 13 patients with metastatic castration-resistant prostate cancer (mCRPC) were retrospectively analyzed. Pharmacokinetic/dynamic parameters were simultaneously fitted in a Bayesian framework to PET/CT activity concentrations, planar scintigraphy data and tumor volumes prior and post (6 weeks) therapy. The method was validated using the leave-one-out Jackknife method. The tumor volume post therapy was predicted based on pre-therapy PET/CT imaging and PBPK/PD modeling. Results: The relative deviation of the predicted and measured tumor volume for PSMA-positive tumor cells (6 weeks post therapy) was 1±40% excluding one patient (PSA negative) from the population. The radiosensitivity for the PSA positive patients was determined to be 0.0172±0.0084 Gy-1. Conclusion: The proposed method is the first attempt to solely use PET/CT and modeling methods to predict the PSMA-positive tumor volume after radioligand therapy. Internal validation shows that this is feasible with an acceptable accuracy. Improvement of the method and external validation of the model is ongoing.

In peptide receptor radionuclide therapy with ⁹⁰Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity, which can be safely administered in many patients. A higher tumor to kidneys 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 to 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 physiological parameters were taken from the literature. Individual model parameters were fitted to series (N = 12) of planar gamma camera and serum measurements (¹¹¹In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, the tumor, liver, spleen and red marrow biologically effective doses (BED) for a maximal kidney BED (20 Gy2.5) were determined 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 < 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 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, the optimal amount and pertaining activity was identified 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 ⁹⁰Y-DOATATE therapy, both, the administered amount of peptide and activity should be optimized in treatment planning using the herein proposed method. This approach could also be adapted for therapy with other peptides.