Physiologically based pharmacokinetic modeling of (18)F-SiFAlin-Asp3-PEG1-TATE in AR42J tumor bearing mice

Christian Maaß; Jose Ricardo Avelar Rivas; Ali Asgar Attarwala; Deni Hardiansyah; Sabrina Niedermoser; Shanna Litau; Carmen Wängler; Björn Wängler; Gerhard Glatting

doi:10.1016/j.nucmedbio.2016.01.001

Physiologically based pharmacokinetic modeling of (18)F-SiFAlin-Asp3-PEG1-TATE in AR42J tumor bearing mice

Nucl Med Biol. 2016 Apr;43(4):243-6. doi: 10.1016/j.nucmedbio.2016.01.001. Epub 2016 Jan 7.

Authors

Christian Maaß¹, Jose Ricardo Avelar Rivas², Ali Asgar Attarwala², Deni Hardiansyah², Sabrina Niedermoser³, Shanna Litau⁴, Carmen Wängler⁵, Björn Wängler³, Gerhard Glatting²

Affiliations

¹ Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany. Electronic address: cmaass@mit.edu.
² Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
³ Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
⁴ Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany; Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
⁵ Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.

PMID: 27067044
DOI: 10.1016/j.nucmedbio.2016.01.001

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) is commonly performed in the treatment of neuroendocrine tumors (NET), where somatostatin analogs (DOTATATE) are radiolabeled with (90)Y, (68)Ga or (111)In for pre-therapeutic and therapeutic purposes. Quantitative evaluation of the biokinetic data can be performed by using physiologically based pharmacokinetic (PBPK) models. Knowledge about the biodistribution in a pre-clinical setting would allow optimizing the translation from bench to bedside. The aim of this study was to develop a PBPK model to describe the biodistribution of a novel sst2-targeting radiotracer.

Methods: Biokinetic data of six mice after injection of (18)F-SiFAlin-Asp3-PEG1-TATE were investigated using two PBPK models. The PBPK models describe the biodistribution of the tracer in the tumor, kidneys, liver, remainder and whole body via blood flow to these organs via absorption, distribution, metabolism and excretion. A recently published sst2 PBPK model for humans (model 1) was used to describe the data. Physiological information in this model was adapted to that of a mouse. Model 1 was further modified by implementing receptor-mediated endocytosis (model 2). Model parameters were fitted to the biokinetic data of each mouse. Model selection was performed by calculating Akaike weights wi using the corrected Akaike Information Criterion (AICc).

Results: The implementation of receptor-mediated endocytosis considerably improved the description of the biodistribution (Akaike weights w1=0% and w2=100% for model 1 and 2, respectively). The resulting time-integrated activity coefficients determined by model 2 were for tumor (0.05 ± 0.02) h, kidneys (0.11 ± 0.01) h and liver (0.02 ± 0.01) h.

Conclusion: Simply downscaling a human PBPK model does not allow for an accurate description of (18)F-SiFAlin-Asp3-PEG1-TATE in mice. Biokinetics of this tracer can be accurately and adequately described using a physiologically based pharmacokinetic model including receptor-mediated endocytosis. Thus, an optimized translation from bench to bedside is possible.

Keywords: Mice; Neuroendocrine tumor (NET); Peptide receptor radionuclide therapy (PRRT); Physiologically based pharmacokinetic (PBPK) modeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Humans
Mice
Models, Biological*
Neuroendocrine Tumors / metabolism*
Neuroendocrine Tumors / pathology
Peptides / chemistry
Peptides / metabolism
Peptides / pharmacology*
Receptors, Somatostatin / metabolism
Somatostatin / chemistry
Somatostatin / metabolism
Somatostatin / pharmacokinetics*
Tissue Distribution

Substances

18F-SiFAlin-Asp(3)-PEG(1)-TATE
Peptides
Receptors, Somatostatin
somatostatin receptor 2, mouse
Somatostatin