title: Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults.
abstract: OBJECTIVE
  Technetium etarfolatide ((99m)Tc-EF) is a radioactive diagnostic imaging agent that was developed to assess the expression of folate receptors in tumors. Administering folic acid prior to the administration of (99m)Tc-EF has been shown to improve SPECT images. Here, we conducted a phase I clinical trial to assess the safety, pharmacokinetics, and radiation dosimetry of (99m)Tc-EF injection following pre-administration of folic acid in healthy Japanese male adults.
  
  
  METHODS
  Six healthy Japanese male adults were enrolled in the study. Folic acid was intravenously administered, followed 1-3 min later by an intravenous injection of (99m)Tc-EF (740 MBq ± 20 %). Assessments of subjective symptoms and objective findings, electrocardiograms, physical examination, and laboratory tests were performed before and up to 7 days after the injection to assess the safety of (99m)Tc-EF. Blood and urine collections and whole-body planar imaging were conducted at various time points up to 24 h after the injection to assess the pharmacokinetics of (99m)Tc-EF. The internal radiation dosimetry was calculated based on the pharmacokinetics results using the MIRD method.
  
  
  RESULTS
  Five adverse events were observed in three subjects (50 %) after administration of the folic acid and (99m)Tc-EF, while these events were mild and non-serious. Of those five events, three were considered to be related to the administered agents. The radioactivity in blood rapidly decreased and showed a biphasic profile. The activity of (99m)Tc-EF at 5 min post injection was largest in the bone marrow, followed by the liver and kidneys, and had decreased within 24 h in all organs/tissues without appreciable retention. The pharmacokinetics results suggested that (99m)Tc-EF was mainly eliminated by kidney. The results also suggested that when administered at 925 MBq of (99m)Tc-EF, which is the maximum dose generally used for clinical trials in other countries, the corresponding effective dose of (99m)Tc-EF is equal to or less than those determined for the current radioactive diagnostic imaging agents.
  
  
  CONCLUSIONS
  The results of this study assessing the safety and radiation dosimetry of (99m)Tc-EF with folic acid pre-administration suggested that folic acid and (99m)Tc-EF should be appropriate for further studies. No pharmacokinetics concerns were noted.
authors.affiliation: Biomedical Research Center, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8642, Japan. yamada-y@insti.kitasato-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Biomedical Research Center, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8642, Japan. nakatani@insti.kitasato-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakatani
authors.affiliation: Department of Diagnostic Radiology and Interventional Radiology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan. yanaq@insti.kitasato-u.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yanaihara
authors.affiliation: Clinical Development Department, Nihon Medi-Physics Co., Ltd., Tokyo, Japan. masahiro_omote@nmp.co.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Omote
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D058973:Folate Receptors, GPI-Anchored / Q000032:analysis; D005492:Folic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007564:Japan; D008297:Male; D015394:Molecular Structure; D015609:Organotechnetium Compounds / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D013997:Time Factors; D014803:Vitamin B Complex / Q000008:administration & dosage*; D051598:Whole Body Imaging / Q000379:methods
chemical_list: D058973:Folate Receptors, GPI-Anchored; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C000588984:technetium 99m etarfolatide; D014803:Vitamin B Complex; D005492:Folic Acid
keywords: 99mTc-etarfolatide; Companion diagnostics; Folate receptor; Phase I; SPECT