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Effective in vitro evaluation of the risk of histamine release related to valemetostat tosylate using MRGPRX2-expressing cells.
Hamamura-Yasuno, Eri; Kinoshita, Junzo; Goto, Koichi; Fujimoto, Kazunori; Pignatello, Michael; Tsuchiya, Yoshimi; Mori, Kazuhiko.
Afiliação
  • Hamamura-Yasuno E; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Kinoshita J; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Goto K; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Fujimoto K; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Pignatello M; Medicinal Safety, Precision Medicine, Daiichi Sankyo, Inc., USA.
  • Tsuchiya Y; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Mori K; Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd.
J Toxicol Sci ; 49(4): 163-174, 2024.
Article em En | MEDLINE | ID: mdl-38556353
ABSTRACT
Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species in the pseudo-allergic reactions, no platform for evaluating a human risk of the pseudo-allergic reactions observed in nonclinical studies has been established. Valemetostat tosylate, developed as an anti-cancer drug, induced histamine release in a nonclinical study with dogs. The purpose of the current study was to identify the mechanism and assess the human risk of valemetostat-tosylate-induced histamine release using dog and human MRGPRX2-expressing cells. In an experiment with human or dog MRGPRX2-expressing cells, valemetostat tosylate caused activation of human and dog MRGPRX2. Importantly, the EC50 for dog MRGPRX2 was consistent with the Cmax value at which histamine release was observed in dogs. Furthermore, the EC50 for human MRGPRX2 was ca. 27-fold higher than that for dog MRGPRX2, indicating a species difference in histamine-releasing activity. In a clinical trial, histamine release was not observed in patients receiving valemetostat tosylate. In conclusion, an in vitro assay using human and animal MRGPRX2-expressing cells would be an effective platform to investigate the mechanism and predict the human risk of histamine release observed in nonclinical studies.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Liberação de Histamina / Anafilaxia Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Liberação de Histamina / Anafilaxia Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article