title: Physiologically Based Pharmacokinetic Modeling Is Essential in 90Y-Labeled Anti-CD66 Radioimmunotherapy.
abstract: BACKGROUND
  Radioimmunotherapy (RIT) with 90Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of 111In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients.
  
  
  OBJECTIVE
  The aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in 90Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model.
  
  
  METHODS
  Two new PBPK models were developed considering fully, half and non-immunoreactive antibodies and constraints for estimating the RM antigen number. Both models were fitted to gamma camera and serum measurements of 27 patients. Akaike weights were used for model averaging. Time-integrated activity coefficients for total body, liver, spleen, RM and serum were calculated. Model-based predictions of the serum biokinetics during therapy were compared to actual measurements.
  
  
  RESULTS
  Variability of the RM time-integrated activity coefficients ((37.3 ± 7.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-25 ± 16)%. The prediction accuracy of these differences using the refined PBPK models was (-3 ± 20)%.
  
  
  CONCLUSIONS
  Individual treatment is needed due to biological differences between patients in RIT with 90Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models.
authors.affiliation: Department of Nuclear Medicine, Ulm University, 89070, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kletting
authors.affiliation: Medical Radiation Physics/Radiation Protection, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maaß
authors.affiliation: Department of Nuclear Medicine, Ulm University, 89070, Ulm, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Reske
authors.affiliation: Department of Nuclear Medicine, Ulm University, 89070, Ulm, Germany.
authors.forename: Ambros J
authors.initials: AJ
authors.lastname: Beer
authors.affiliation: Medical Radiation Physics/Radiation Protection, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Glatting
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D006801:Humans; D007553:Isotope Labeling; D007938:Leukemia / Q000532:radiotherapy*; D008954:Models, Biological; D016499:Radioimmunotherapy; D013997:Time Factors; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D015021:Yttrium Radioisotopes