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Identification and quantitative structure–activity relationship assessment of trace chemical impurities contained in the therapeutic formulation of [64Cu]Cu-ATSM
https://repo.qst.go.jp/records/85109
https://repo.qst.go.jp/records/8510934a9b802-2e7a-4b62-a6ef-9ca7dfce5696
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2021-12-03 | |||||
| タイトル | ||||||
| タイトル | Identification and quantitative structure–activity relationship assessment of trace chemical impurities contained in the therapeutic formulation of [64Cu]Cu-ATSM | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Chika, Igarashi
× Chika, Igarashi× Hiroki, Matsumoto× Masashi, Takahashi× Fukiko, Hihara× Tomoko, Tachibana× Zhang, Ming-Rong× Hiroaki, Kurihara× Tatsuya, Higashi× Yukie, Yoshii× Chika, Igarashi× Hiroki, Matsumoto× Masashi, Takahashi× Fukiko, Hihara× Tomoko, Tachibana× Zhang, Ming-Rong× Tatsuya, Higashi× Yukie, Yoshii |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | 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. |
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| 書誌情報 |
Nuclear Medicine and Biology 巻 108-109, p. 10-15, 発行日 2022-02 |
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| 出版者 | ||||||
| 出版者 | Elsevier | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0969-8051 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1016/j.nucmedbio.2022.02.001 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | https://www.sciencedirect.com/science/article/pii/S0969805122000129 | |||||
