QT PRODACT : Comparison of Non-clinical Studies for Drug-Induced Delay in Ventricular Repolarization and Their Role in Safety Evaluation in Humans
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概要
- 論文の詳細を見る
Drug concentrations that would prolong repolarization parameters by 10%, including action potential duration (APD90, APD30 – 90), in in vitro assays using guinea-pig papillary muscle and QTc intervals in in vivo assays using conscious dogs, conscious monkeys, and anesthetized dogs were compared. Although, both the in vitro and in vivo assays showed concentration-dependent responses for compounds that have been classified as torsadogenic in humans, only a weak correlation in EC10 values was observed between the in vitro and in vivo assays. Among the in vivo QT assays, the EC10 values obtained from conscious dogs, conscious monkeys, and anesthetized dogs correlated well with each other, but the EC10 values in monkeys were somewhat lower in comparison to those in dogs. When in vivo QT assay EC10 values were compared to the respective human effective therapeutic plasma concentration (ETPC), the ratios of EC10 values to ETPCs were less than 20 for most torsadogenic compounds. In conclusion, the relationships between the extent of QTc interval prolongation and the concentration of drugs was highly consistent among the three in vivo models, suggesting that the ratios of EC10 values in in vivo QT assays are useful for estimating the safety margin of drugs that prolong the QTc interval.
- 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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OMATA Takeshi
Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd.
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KASAI Chieko
Drug Safety Research Laboratories, Astellas Pharma Inc.
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HASHIMOTO Munehiro
Nonclinical Regulatory Sciences, Worldwide Safety Sciences, Global Research & Development, Nagoya La
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HOMBO Toshiyasu
Drug Safety Research Laboratories, Astellas Pharma Inc.
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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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Kasai Chieko
Drug Safety Research Laboratories Astellas Pharma Inc.
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Kii Yoshihide
Safety Research Laboratories Dainippon Sumitomo Pharma Co. Ltd.
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Omata Takeshi
Central Research Laboratories Zeria Pharmaceutical Co. Ltd.
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Yamada Kiyoshi
Pharmaceutical Research Laboratories Toray Industries Inc.
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Hashimoto Munehiro
Nonclinical Regulatory Sciences Worldwide Safety Sciences Global Research & Development Nagoya L
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Hombo Toshiyasu
Drug Safety Research Laboratories Astellas Pharma Inc.
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Yamamoto Keiji
Non-clinical Evaluation Subcommittee Drug Evaluation Committee Japan Pharmaceutical Manufactures Ass
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