In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for ²¹²Pb-labeled somatostatin analogs (²¹²Pb-SSTA). The model describes pharmacokinetics of ²¹²Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting ²¹²Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on ²¹²Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on ²¹²Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The ²¹²Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.

Background: Targeted α particle therapy using long-lived in vivo α particle generators is cytotoxic to target tissues. However, the redistribution of released radioactive daughters through the circulation should be considered. A mathematical model was developed to describe the physicochemical kinetics of ²¹²Pb-labeled pharmaceuticals and its radioactive daughters. Materials and Methods: A bolus of ²¹²Pb-labeled pharmaceuticals injected in a developed compartmental model was simulated. The contributions of chelated and free radionuclides to the total released energy were investigated for different dissociation fractions of ²¹²Bi for different chelators, for example, 36% for DOTA. The compartmental model was applied to describe a ²¹²Bi retention study and to assess the stability of the ²¹²Bi-1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (²¹²Bi-DOTAM) complex after β⁻ decay of ²¹²Pb. Results: The simulation of the injection showed that α emissions contribute 75% to the total released energy, mostly from ²¹²Po (72%). The simulation of the ²¹²Bi retention study showed that (16 ± 5)% of ²¹²Bi atoms dissociate from the ²¹²Bi-DOTAM complexes. The fractions of energies released by free radionuclides were 21% and 38% for DOTAM and DOTA chelators, respectively. Conclusion: The developed α particle generator model allows for simulating the radioactive kinetics of labeled and unlabeled pharmaceuticals being released from the chelating system due to a preceding disintegration.

Background: α particle emitting bismuth ( ²¹² Bi) as decay product of ²¹² Pb-labeled pharmaceuticals has been effective in targeted α particle therapy (TAT). Estimating the contribution of ²¹² Bi released from its chelator to the absorbed doses in nontarget tissues is challenging in TAT. Physiologically based pharmacokinetic (PBPK) modeling can help overcome this limitation. Therefore, a whole-body ²¹² Bi–PBPK model was developed to describe the pharmacokinetics (PKs) of ²¹² Bi in rats. Materials and Methods: The rat ²¹² Bi–PBPK model was implemented using the modeling software SAAM II with data and parameter values from the literature. Besides other mechanisms, ²¹² Bi interactions with red blood cells, high molecular weight plasma protein, and intracellular biological thiols are described. Important PK parameters were fitted to time–activity data. Absorbed dose coefficients (ADCs) were calculated for injecting 0.774 fmol of ²¹² Bi. Results: ²¹² Bi uptake rates of liver, bone, small intestine, bone marrow, skin, and muscle were (0.86 ± 0.13), (3.85 ± 0.63), (0.27 ± 0.05), (1.44 ± 0.29), (0.04 ± 0.01), and (0.007 ± 0.007) per min with corresponding ADCs of 0.09, 0.03, 0.03, 0.07, 0.01, and 0.003 mGy/kBq, respectively. An ADC of 0.70 mGy/kBq was determined for kidneys. Conclusions: Kidneys are the dose-limiting organs in ²¹² Bi-based TAT. The ²¹² Bi–PBPK model is an effective tool to investigate the ²¹² Bi biodistribution in murine models. Integrating the ²¹² Bi–PBPK model into other murine and human PBPK models of α particle generators can help study the efficacy and safety of TAT.