Preclinical Pharmacokinetic and Safety Studies of Copper-Diacetyl-Bis(N4-Methylthiosemicarbazone) (Cu-ATSM): Translational Studies for Internal Radiotherapy

Abstract

Hypoxia plays important roles in the prognosis of malignant brain tumors such as glioblastoma because it causes drug delivery deficiencies and the induction of hypoxia-inducible factor-1α in tumor cells. Extensive hypoxic areas are associated with poor prognosis of these fatal diseases. We previously reported that multiple administrations of the hypoxia-targeted internal radiotherapy agent 64 Cu-diacetyl-bis( N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM), four times at intervals of 1 or 2 weeks, show antitumor effects in glioblastoma without treatment-related adverse events. Before initiating clinical trials, preclinical safety studies using Cu-ATSM composed of stable isotopes and its precursor ATSM were required to understand the potential risks of systemic and repeated chemical exposure of our investigational drug. In this study, the concentrations of Cu-ATSM and ATSM in mouse plasma after intravenous administration were determined by liquid chromatography–tandem mass spectrometry, and the half-lives were estimated to be 21.5 and 22.4 minutes for Cu-ATSM and ATSM, respectively. Based on this result, approach 2 of the current ICH M3 [R2] guideline was adopted, and a 7-day intravenous toxicity study was conducted in mice. Cu-ATSM and ATSM in a ratio of 2:25 mimicking our current investigational drug was used, and no adverse effects were observed when Cu-ATSM and ATSM were administered at 81 μg/kg. These results and those of previous studies suggest that our current investigational drug formulation containing Cu-ATSM and ATSM at a dose of 15 μg can be safely administered to patients once per week for 4 weeks for treatment with 64 Cu-ATSM.

Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms

“…Similar therapeutic effects has also been demonstrated with [ 64 63 Cu and 65 Cu) and free H 2 -ATSM in a preclinical mouse study. Therapeutic administration of stable [Cu(ATSM)] and H 2 -ATSM in a ratio of 2:25 was found to be safe for patients when given as 15 μg once per week for 4 weeks [63]. In addition, [ 64 Cu][Cu(ATSM)] therapy have been shown to be a novel approach to enhance cancer treatment efficiency concomitantly with bevacizumab in a human colon carcinoma xenograft model, where the repeated use of bevacizumab has caused decreased tumor vascularization and tumor hypoxia.…”

“…It was found that exposure of [ 64 Cu]CuCl 2 inhibits the neurosphere-forming ability of tumor cells, a prerequisite for the formation of tumor masses [29]. Similar therapeutic effects has also been demonstrated with [ 64 63 Cu and 65 Cu) and free H 2 -ATSM in a preclinical mouse study. Therapeutic administration of stable [Cu(ATSM)] and H 2 -ATSM in a ratio of 2:25 was found to be safe for patients when given as 15 μg once per week for 4 weeks [63].…”

[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

“…2b) is a biosimilar and only releases the exogenously bound Cu under hypoxic conditions. Both Cu-ATSM and ATSM are quickly cleared from the circulation with corresponding half-lives (T 1/2 ) of 21.5 and 22.4 min, respectively [38]. The BBB is a highly selective gateway regulating the influx and efflux of molecules from the systemic circulation into the brain and in the reverse direction.…”

“…Administration of penicillamine, a heavy metal chelator, could reduce radiation absorption doses in critical organs such as the liver and small intestine [72]. Different formulations of [ 64 Cu]Cu-ATSM have been developed and validated by two research groups for diagnostic and theranostic applications, respectively [38,63]. The potential risk associated with the chemical impurities from [ 64 Cu]Cu-ATSM degradation is negligible, even in a therapeutic dose of [ 64 Cu]Cu-ATSM [73].…”