A physiologically based pharmacokinetic model for in vivo alpha particle generators targeting neuroendocrine tumors in mice

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 for²¹²Pb-labeled somatostatin analogs (²¹²Pb-SSTA). The model describes pharmacokinetics of²¹²Pb-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-emitting²¹²Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on²¹²Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on²¹²Bi-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. The²¹²Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.