Identification and quantitative structure-activity relationship assessment of trace chemical impurities contained in the therapeutic formulation of [64Cu]Cu-ATSM.

Abstract

BACKGROUND:

[64Cu]Cu-diacethyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) is a radioactive hypoxia-targeting therapeutic agent, and the efficacy and safety of [64Cu]Cu-ATSM in the treatment of malignant brain tumors are evaluated in clinical trials. For the clinical application of [64Cu]Cu-ATSM, we determined a drug formulation incorporating a stabilizer against radiolysis and confirmed its radiochemical stability. This study aimed to identify trace chemical impurities derived from the degradation of ATSM contained in the [64Cu]Cu-ATSM investigational drug formulation and assess their potential hazards by quantitative structure-activity relationship (QSAR) assessment.

METHODS:

We hypothesized that the chemical impurities contained in the [64Cu]Cu-ATSM formulation were derived from the degradation of ATSM. Therefore, we first identified the degradants of ATSM using LC-MS/MS. ATSM was dissolved with the drug formulation of [64Cu]Cu-ATSM, except for 64Cu, and analyzed by LC-MS/MS at 0 and 48 h after sample preparation. Subsequently, the chemical impurities contained in the [64Cu]Cu-ATSM formulation were measured at 0, 5, and 24 h after preparation by HPLC, and the results were compared to the degradants of ATSM. The potential hazards of the chemical impurities contained in the [64Cu]Cu-ATSM formulation were assessed using the QSAR Toolbox (ver. 4.3).

RESULTS:

Six ATSM degradants were detected and identified by LC-MS/MS analysis, indicating that the functional groups around the nitrogen and sulfur atoms of ATSM were affected. The same peaks were detected as trace chemical impurities in the [64Cu]Cu-ATSM formulation at 24 h, while no apparent peaks were detected at 0 and 5 h. The estimated LD50 values of these chemical impurities showed 4.31 mg/kg or more by QSAR assessment. In contrast, the estimated amount of each chemical impurity exposed to patients was 31.8 ng/kg or less per dose. The smallest margin between the amount of chemical impurities and smallest estimated LD50 value of the corresponding impurity was a ratio of approximately 1:700,000.

CONCLUSIONS:

We identified trace chemical impurities derived from ATSM in the [64Cu]Cu-ATSM formulation. This suggests that the potential risk of the systemic exposure of patients to these chemical impurities is substantially low.

• Authors: Chika Igarashi, Hiroki Matsumoto, Masashi Takahashi, Fukiko Hihara, Tomoko Tachibana, Ming-Rong Zhang, Hiroaki Kurihara, Tatsuya Higashi, Yukie Yoshii
• Journal: Nuclear medicine and biology (Nucl Med Biol) 2022 May-Jun Vol. 108-109 Pg. 10-15 ISSN: 1872-9614 [Electronic] United States
• PMID: 35168008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Coordination Complexes
• Copper Radioisotopes
• Organometallic Compounds
• Thiosemicarbazones
• copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)

Topics

• Chromatography, Liquid
• Coordination Complexes
• Copper Radioisotopes
• Humans
• Organometallic Compounds
• Quantitative Structure-Activity Relationship
• Tandem Mass Spectrometry
• Thiosemicarbazones