A physiologically-based pharmacokinetic model for sstr2-targeting [²¹²Pb]-labeled ligands in mice.

Aim: Alpha emitter-based peptide receptor radionuclide therapy (α-PRRT) is an effective treatment for metastatic inoperable neuroendocrine tumors (NETs). ²¹²Pb serves as a promising in vivo source of the short-lived alpha emitter ²¹²Bi. Application of cytotoxic alpha particles of high linear energy transfer reduces nephrotoxicity and facilitates the overcoming of radioresistance of NETs to beta emitters in PRRT. However, quantitative analysis of the biodistribution of in vivo alpha generators and cytotoxic alpha emitting daughters in the body and their contribution to the total tissue-absorbed doses is essential to assess the efficacy and safety of α-PRRT. Mathematical modeling enables cost-free, animal-free studies of the pharmacokinetics of in vivo alpha generators targeting the somatostatin receptor type 2 (sstr2). Therefore, a first physiologically-based pharmacokinetic (PBPK) model for describing the pharmacokinetics and dosimetry of in vivo alpha generators and their radioactive products is presented for xenografted mice in α-PRRT.

Methods: A whole-body ²¹²Pb-PBPK model of in vivo alpha generator in mice was developed and implemented in both modeling software SAAM II version 2.3 (The Epsilon Group, TEG, USA) and Simbiology/MATLAB (MATLAB R2020a, The MathWorks, Inc). The ²¹²Pb-PBPK model describes all relevant physiological mechanisms (blood flow, diffusion, specific and non-specific uptakes, internalization, recycling and excretion) and physicochemical properties (physical decay and radiolabeling stability) with parameter values from the literature. For validation, the time activity data were simulated in both programs and compared for the same parameterization and model input. The PK parameters in the ²¹²Pb-PBPK model were estimated using [²¹²Pb]Pb-DOTAMTATE biokinetic data in mice (n = 5) bearing 300 mm³ AR42J rat xenograft after intravenous administration of 0.0013 nmol (0.169 MBq) of [²¹²Pb]Pb-DOTAMTATE [1]. Dosimetry simulations for bound and unbound in vivo generators and free radionuclides were performed in Simbiology after integrating a ²¹²Bi-PBPK model into the evaluated ²¹²Pb-PBPK model.

Results: The developed model could successfully describe the experimental data in both programs. The fitted curves were good by visual inspection. The simulation results of both programs were quite similar with a relative deviation of 1 %. The tumor plasma flow-rate were (0.25 ± 0.20) ml/min/g. The sstr2 densities in tumor, kidneys, liver, pancreas, spleen and lung were (6.1 ± 0.9), (3.0 ± 0.3), (0.10 ± 0.02), (4.0 ± 1.1), (0.56 ± 0.04), (1.39 ± 0.04) nmol/l, with absorbed dose coefficients (ADC) of 0.10, 0.06, 0.004, 0.06, 0.01, and 0.03 Gy/kBq, respectively.

Conclusions: The developed ²¹²Pb-PBPK model allows for simulating the biokinetics of in vivo alpha particle generators targeting sstr2. The ²¹²Pb-PBPK model can address concerns about the fate of the distributed free radioactive daughters and their contribution to the overall absorbed dose to non-target tissues. The ability of the model to estimate important physiological parameters and subsequently predict optimal dosing regimens will reduce the required time for translation from bench to bedside. Also, the model allows for generating hypotheses for experiments leading to improve α-PRRT for NET. [1]. Stallons, T. A. R., et al. (2019). Molecular Cancer Therapeutics 18(5): 1012-1021.