title: Preclinical pharmacokinetics, biodistribution, radiation dosimetry and acute toxicity studies required for regulatory approval of a Clinical Trial Application for a Phase I/II clinical trial of (111)In-BzDTPA-pertuzumab.
abstract: BACKGROUND
  (111)In-BzDTPA-pertuzumab is a novel imaging probe for detecting changes in HER2 expression in breast cancer (BC) caused by treatment with trastuzumab (Herceptin). Our aim was to evaluate the pharmacokinetics, normal tissue biodistribution, radiation dosimetry and acute toxicity of (111)In-BzDTPA-pertuzumab in non-tumor bearing mice in order to obtain regulatory approval to advance this agent to a first-in-humans Phase I/II clinical trial.
  
  
  METHODS
  Biodistribution and pharmacokinetic studies were performed in non-tumor bearing Balb/c mice injected i.v. with (111)In-BzDTPA-pertuzumab (2.5MBq; 2μg). The cumulative number of disintegrations per source organ derived from the biodistribution data was used to predict the radiation absorbed doses in humans using OLINDA/EXM software. Acute toxicity was studied at two weeks post-injection of (111)In-BzDTPA-pertuzumab (1.0MBq, 20μg) with comparison to control mice injected with unlabeled BzDTPA-pertuzumab (20μg) or Sodium Chloride Injection USP. The dose of (111)In-BzDTPA-pertuzumab corresponded to 23-times the human radioactivity dose and 10-times the protein dose on a MBq/kg and mg/kg basis, respectively. Toxicity was assessed by monitoring body mass, complete blood cell count (CBC), hematocrit (Hct), hemoglobin (Hb), serum creatinine (SCr) and alanine aminotransferease (ALT) and by histopathological examination of tissues at necropsy.
  
  
  RESULTS
  (111)In-BzDTPA-pertuzumab exhibited a biphasic elimination from the blood with a distribution half-life (t1/2α) of 3.8h and an elimination half-life (t1/2β) of 228.2h. The radiopharmaceutical was distributed mainly in the blood, heart, lungs, liver, kidneys and spleen. The projected whole-body radiation absorbed dose in humans was 0.05mSv/MBq corresponding to a total of 16.8mSv for three separate administrations of (111)In-BzDTPA-pertuzumab (111MBq) planned for the Phase I/II trial. There were slight changes in Hb and SCr levels associated with administration of multiples of the human dose in healthy Balb/c mice but no histopathological abnormalities were noted in any tissues. There were no significant differences in body mass between mice injected with (111)In-BzDTPA-pertuzumab or control mice.
  
  
  CONCLUSIONS
  Preclinical studies predicted that (111)In-BzDTPA-pertuzumab is safe to administer to humans at a dose of 111MBq (5mg). The radiopharmaceutical exhibited preclinical pharmacokinetic, biodistribution and radiation dosimetry properties suitable for advancement to a first-in-humans clinical trial.
  
  
  CONCLUSIONS
  The results of these studies supported the regulatory approval by Health Canada of (111)In-BzDTPA-pertuzumab for a Phase I/II clinical trial of for imaging the response of patients with metastatic BC to treatment with trastuzumab combined with chemotherapy (PETRA trial; ClinicalTrials.gov identifier: NCT01805908).
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Lam
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada.
authors.forename: Conrad
authors.initials: C
authors.lastname: Chan
authors.affiliation: Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada; Campbell Family Institute for Breast Cancer Research and Laboratory Medicine Program, University Health Network, Toronto, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Done
authors.affiliation: Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Ontario, Canada; Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address: raymond.reilly@utoronto.ca.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017277:Drug Approval; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D051379:Mice; D004369:Pentetic Acid / Q000737:chemistry; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D012926:Social Control, Formal; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D004369:Pentetic Acid; C485206:pertuzumab
keywords: Clinical trial application; Indium-111; Pertuzumab; Pharmacokinetics; Radiation dosimetry; Toxicology