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

Nouran R R Zaid; Peter Kletting; Gordon Winter; Vikas Prasad; Ambros J Beer; Gerhard Glatting

doi:10.3390/pharmaceutics13122132

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

Pharmaceutics. 2021 Dec 10;13(12):2132. doi: 10.3390/pharmaceutics13122132.

Authors

Nouran R R Zaid^{1

2}, Peter Kletting^{1

3}, Gordon Winter³, Vikas Prasad³, Ambros J Beer³, Gerhard Glatting^{1

3}

Affiliations

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.

Abstract

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.

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

Abstract

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