QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals.
The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n=4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma/serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals.
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Tokyo, Japan. toyosisg@otsukakj.co.jp
Shigeki
S
Toyoshima
Akihiro
A
Kanno
Tetsuya
T
Kitayama
Koji
K
Sekiya
Keiko
K
Nakai
Masao
M
Haruna
Terumasa
T
Mino
Hiroyasu
H
Miyazaki
Koji
K
Yano
Keiji
K
Yamamoto
D000818:Animals; D016208:Databases, Factual; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000097:blood; D010599:Pharmacokinetics; D013686:Telemetry
D004364:Pharmaceutical Preparations