QT PRODACT : In Vivo QT Assay in Anesthetized Dog for Detecting the Potential for QT Interval Prolongation by Human Pharmaceuticals
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概要
- 論文の詳細を見る
The purpose of this study was to assess the utility of the isoflurane-anesthetized dog model for detecting the potential for QT interval prolongation by human pharmaceuticals. The effects of 10 positive compounds with torsadogenic potential, 8 negative compounds with little torsadogenic potential, and dl-sotalol as a common positive compound were evaluated in 5 facilities in accordance with the common protocol approved by QT PRODACT. Each test compound was cumulatively infused into male beagle dogs anesthetized with isoflurane. Surface lead II ECG, blood pressure, and plasma concentrations for the positive compounds were measured. Repeated administration of the vehicle examined in each facility before the start of the experiments resulted in a slight, but not significant, change in corrected QT (QTc) interval, indicating that this model only shows slight experimental variation. Although an inter-facility variability in the extent of dl-sotalol-induced QT interval prolongation was observed, dl-sotalol significantly prolonged QTc interval in all facilities. All positive compounds significantly prolonged QTc interval at plasma levels up to 10 times those in patients who developed prolonged QTc interval or TdP, whereas no negative compounds did so. These data suggest that the in vivo QT assay using the anesthetized dog is a useful model for detecting the potential for QT interval prolongation by human pharmaceuticals. Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A3
- 社団法人 日本薬理学会の論文
- 2005-12-31
著者
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Yamamoto Keiji
日本製薬工業協会
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Yamamoto Keiji
Development Research Center Takeda Pharmaceutical Co. Ltd.
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Yamamoto Keiji
Non-clinical Evaluation Subcommittee Drug Evaluation Committee Japan Pharmaceutical Manufactures Ass
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MIYAZAKI Hiroyasu
Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co., Ltd.
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TASHIBU Hiroyuki
Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd.
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AOKI Kumiko
Pharmacology & Safety Research Department, Teijin Pharma Ltd.
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AKIE Yasuki
Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd.
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Yamamoto Keiji
Development Research Center Takeda Pharmaceutical Co.
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Yamamoto Keiji
Drug Safety Research Laboratories Tanabe Seiyaku Co. Ltd.
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Yano Koji
Drug Safety Research Laboratories Tanabe Seiyaku Co. Ltd.
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Aoki Kumiko
Pharmacology & Safety Research Department Teijin Pharma Ltd.
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Akie Yasuki
Kobuchisawa Laboratories Fuji Biomedix Co. Ltd.
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Kii Yoshihide
Safety Research Laboratories Dainippon Sumitomo Pharma Co. Ltd.
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Yamada Kiyoshi
Pharmaceutical Research Laboratories Toray Industries Inc.
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Miyazaki Hiroyasu
Tsukuba Safety Assessment Laboratories Banyu Pharmaceutical Co. Ltd.
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Tashibu Hiroyuki
Safety Research Laboratories Dainippon Sumitomo Pharma Co. Ltd.
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Yamamoto Keiji
Non-clinical Evaluation Subcommittee Drug Evaluation Committee Japan Pharmaceutical Manufactures Ass
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