Optimization of imaging and therapy for a radioligand targeting the prostate-specific membrane antigen using a physiologically-based pharmacokinetic model

Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is a promising systemic treatment for metastatic castration-resistant prostate cancer (mCRPC) when conventional treatments are no longer an option. Although PSMA-targeted RLT is a viable treatment option for mCRPC, the effect of therapy varies from patient to patient. The therapeutic effect is generally determined by the absorbed dose and absorbed dose rate in tumors and normal organs, which depend on the choice of radionuclide, ligand properties, and individual patients' biokinetics. Measurement before therapy, e.g., PET/CT, is becoming increasingly essential to accurately estimate the absorbed dose in therapy. Varying ligand amounts, ligand properties, and radionuclides can affect the efficacy of PSMA-targeted imaging and therapy. Inter-patient variability, such as total tumor volume (TTV), must also be considered as it affects the biodistribution of radioligand in the patient. A more detailed understanding of the important parameters affecting imaging and therapy of PSMA-targeted RLT is needed. Therefore, this thesis aimed to investigate 1) the effect of TTV on the biologically effective dose (BED) to tumors and organs at risk (OAR), 2) the effects of ligand amounts, affinities, and internalization on imaging and therapy, and 3) the effects of radionuclide half-lives, ligand affinities, and measurement time points after injection on tumor and background activity. For this purpose, 13 patients with mCRPC treated with 177-Lu-PSMA I&T were included. A physiologically-based whole-body pharmacokinetic (PBPK) model for PSMA-specific ligands was developed based on PSMA-11 and PSMA I&T and implemented in MATLAB® software packages (Simulink and Simbiology). The PBPK model was fitted to biokinetics data of 13 patients to estimate individual patient parameters. The PBPK model with individually estimated parameters (virtual patients) was utilized for the simulations with MATLAB®. The effect of TTV on absorbed dose and BED was investigated by simulating TTVs of 0.1-10 L for tumors and OAR. The activity and amount of ligand to be administered leading to an optimal tumor to kidney ratio were also investigated. The effects of ligand properties on PET/CT imaging and therapy were studied for ligand amounts (1-1000 nmol), association rates kon (0.1-0.01 L/nmol/min), dissociation rates koff (0.1-0.0001 min-1), and internalization rates λint (0.01-0.0001 min-1). The activity was normalized to volume and administered activity for imaging (68Ga-PSMA at 1 h). The absorbed dose of 7.3 GBq 177-Lu-PSMA was calculated for therapy. Three radionuclides with different half-lives 68Ga (t1/2 = 1.13 h), 18F (t1/2 = 1.83 h), and 64Cu (t1/2 = 12.7 h) were simulated for different affinities (dissociation constants KD of 1-0.01 nM). A common ligand amount of 3 nmol investigated the effects of radionuclide half-life and ligand affinity on activity concentration in PET/CT imaging. Activity concentrations were calculated at various time points (1, 2, 3, 4, 8, 12, and 16 h p.i.). Simulated BEDs decreased in tumor lesion (58% ± 18%), kidneys (58% ± 17%), parotid glands (59% ± 16%), and submandibular glands (59% ± 16%) when TTV was increased from 0.3 to 3 L. BED for red bone marrow increased (185% ± 29%). The optimal ligand amount and activity were 273 ± 136 nmol and 10.4 ± 4.4 GBq, respectively, in patients with a TTV greater than 0.3 L. The effects of ligand properties on therapy were greater than those of imaging. The combination of ligand properties (kon = 0.1 L/nmol/min, and koff = 0.01 min-1) resulted in the highest tumor uptake for imaging using commonly used ligand amounts (1-10 nmol). The higher the internalization rate, the higher ligand amount is required for an appropriate tumor-to-kidney ratio in therapy. Choosing the optimal amount of ligand became more crucial as the affinity increased. The maximum tumor uptake was achieved 1 h p. i. for 68-Ga-PSMA in a simulated study on the effect of the radioactive half-life on PET/CT imaging for varied ligand affinities. The maximum tumor uptake was at 1 h p. i. and 2 h p. i. for 18-F-PSMA, for dissociation constants KD = 1 nM and KD = 0.1-0.01 nM, respectively. The maximum tumor uptake for 64-Cu-PSMA was observed at 4 h p.i. for dissociation constant KD = 1 nM, and at 4 h p. i. (9 patients) and 8 h p. i. (4 patients) for higher affinities. Activity concentrations in the tumor increased 1.3-fold for 18F-PSMA (2 h p.i.) compared to 68-Ga-PSMA (1 h p.i.), with insignificant differences for all affinities. The improvements in 64-Cu-PSMA (4 h p. i.) were 2.8 to 3.2-fold for all affinities. The presented results provide essential information to optimize imaging and therapy of PSMA-targeted RLT. It can be concluded that: 1. The total tumor volume strongly influences the absorbed dose and BED in tumors and OAR. Patients with a high tumor burden can receive more activities and ligands without exceeding the tolerable BED for the OAR to improve the therapeutic effect. 2. The higher the ligand affinity, the more important the optimal amount of ligand was chosen. 3. The highest tumor-to-background ratio can be achieved after 4 h in PET/CT with the commonly used ligand amounts of the high-affinity 64-Cu-PSMA target ligands.