A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice


by Nouran R. R. Zaid 1,2,*, Peter Kletting 1,3, Gordon Winter 3, Vikas Prasad 3, Ambros J. Beer 3 and Gerhard Glatting 1,3

1 Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, 89081 Ulm, Germany
2 Biophysics and Medical Imaging Program, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 44839, Palestine
3 Department of Nuclear Medicine, Ulm University, 89081 Ulm, Germany
* Author to whom correspondence should be addressed.

Academic Editors: Matilde Merino-Sanjuán, Virginia Merino Sanjuán and Victor Mangas Sanjuán

Pharmaceutics 2021, 13(12), 2132; https://doi.org/10.3390/pharmaceutics13122132
Received: 15 October 2021 / Revised: 4 December 2021 / Accepted: 7 December 2021 / Published: 10 December 2021

(This article belongs to the Special Issue Physiologically-Based Pharmacokinetics (PBPK) and Biopharmaceutics (PBBM) Modeling)


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. View Full-Text

Keywords: murine PBPK model; neuroendocrine tumors; α-PRRT; in vivo alpha particle generators; [212Pb]Pb-DOTAMTATE