Toxicity study of TEoS-DAZA, a chemical precursor for functional liver imaging with PET/CT

Abstract

Background

N,1,4-Tri(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine (TEoS-DAZA), a novel radiopharmaceutical precursor for a liver-specific 68Ga-based diagnostic radiopharmaceutical, was tested for toxicity in rats to ensure its safe applicability and to fulfil the preclinical requirements in preparation of a clinical study. The study was performed according to EMA draft Guideline on the non-clinical requirements for radiopharmaceuticals, as well as to the so-called microdosing approach of the ICH guideline M3 (R2).

Results

This randomized study was conducted using Wistar rats. The test item was administered intravenously at three different dose levels, the vehicle solution was administered to a separate group as control. Toxicity assessment included a 24 h observation period in three dose groups, and a 14-day recovery period in the high dose group. Animals were monitored regarding clinical behaviour, bodyweight, food and water consumption, additionally undergoing modified IRWIN, grip-strength and beam-walking tests. Following euthanisation, extensive haematological and clinical biochemical parameters were analysed. Necropsy and histopathology were performed. There was no evidence to any test-item related adversities at any dose level. No delayed effects were identified in any animal at the end of the recovery phase. Some small, albeit significant changes in haematology and clinical biochemistry could not be related to the test item administration. The NOAEL of TEoS-DAZA was determined at 1.4 mg/kg bodyweight.

Conclusions

Administration of a thousandfold clinical dose of TEoS-DAZA in rats did not cause any observable adverse events. An injectable solution of [68Ga]Ga-TEoS-DAZA containing 100 µg of the precursor is safe for clinical application to humans from the pharmacological point of view. Subsequent dosimetry studies need to be undertaken to reveal any radiation related toxicity.