QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

Journal of Pharmacological Sciences

Shingo Hizume⁵  Kentaro Ando⁶  Tetsuya Kitayama⁶  Keiko Nakai⁵  Noritsugu Shimizu³  Akihiro Kanno¹  Yoshinori Yamamoto⁵  Kengo Sakamoto⁴  Hironobu Ikeda²  Shin-ichi Kitani⁴  Masakazu Imaizumi⁷  Keiji Yamamoto⁶  Toshiyasu Hombo⁶ 

[1] Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Japan;Research Department, NISSEI BILIS Co., Ltd., Japan;Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd., Japan;Pharmacology & Toxicology Department, Ina Research, Inc., Japan;Pharmacology Division, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., Japan;Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan;Department of Pharmacology, Panapharm Laboratories Co., Ltd., Japan

关键词: safety pharmacology;    cynomolgus monkey;    telemetry assay;    QTc interval;    QT PRODACT;   

DOI  :  10.1254/jphs.QT-A4

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(51)Cited-By(46)Supplementary materials(3)In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n = 3 – 4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett’s formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett’s formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation. Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A4

【 授权许可】

Unknown