title: Physiologically based pharmacokinetic modeling of (18)F-SiFAlin-Asp3-PEG1-TATE in AR42J tumor bearing mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany. Electronic address: cmaass@mit.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Maaß
authors.affiliation: Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Jose Ricardo Avelar
authors.initials: JR
authors.lastname: Rivas
authors.affiliation: Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Ali Asgar
authors.initials: AA
authors.lastname: Attarwala
authors.affiliation: Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Deni
authors.initials: D
authors.lastname: Hardiansyah
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Niedermoser
authors.affiliation: 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.
authors.forename: Shanna
authors.initials: S
authors.lastname: Litau
authors.affiliation: Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wängler
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Wängler
authors.affiliation: Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Glatting
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C000613069:18F-SiFAlin-Asp(3)-PEG(1)-TATE; D010455:Peptides; D017481:Receptors, Somatostatin; C570769:somatostatin receptor 2, mouse; D013004:Somatostatin
keywords: Mice; Neuroendocrine tumor (NET); Peptide receptor radionuclide therapy (PRRT); Physiologically based pharmacokinetic (PBPK) modeling