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.