QT/QTc study conducted in Japanese adult healthy subjects: a novel xanthine oxidase inhibitor topiroxostat was not associated with QT prolongation.
A QT/QTc study was conducted in compliance with ICH E14 guideline to evaluate the effects of a new xanthine oxidase inhibitor topiroxostat in Japanese healthy subjects. Forty-eight Japanese healthy subjects (males 24; females 24) received a single oral dose of topiroxostat (60 or 180 mg), moxifloxacin (400 mg) or placebo in a single-center, double-blind, four-period crossover design. Fridericia's formula (QTcF = QT/RR(0.33) ) was used as a primary method for QT-interval correction. The mean QTcF was prolonged by moxifloxacin, of which largest time-matched difference from placebo administration was 13.6 milliseconds with 90% confidence interval (CI) of 11.2 and 15.9 milliseconds at 4 hours post-dose. The mean QTcF was hardly affected by either dose of topiroxostat, of which largest time-matched difference from placebo administration was 2.9 milliseconds with 90% CI of 0.6 and 5.3 milliseconds at 4 hours post-dose for 60 mg, and 2.3 milliseconds with 90% CI of 0 and 4.7 milliseconds at 1 hour post-dose for 180 mg. The results were essentially the same in the sex subgroup analysis. Moxifloxacin can be used as a positive control for QT/QTc studies in Japanese subjects; and topiroxostat may not cause QT-interval prolongation in males as well as females.
Department of Pharmacology, Faculty of Medicine, Toho University, Omori-Nishi, Ota-ku, Tokyo, Japan; Yamanashi Research Center of Clinical Pharmacology, Iwasa-cho, Fuefuki, Yamanashi, Japan.
Atsushi
A
Sugiyama
Hiroya
H
Hashimoto
Yuji
Y
Nakamura
Tomoe
T
Fujita
Yuji
Y
Kumagai
D000328:Adult; D044466:Asian People; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009570:Nitriles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D055815:Young Adult
D024841:Fluoroquinolones; D009570:Nitriles; D011725:Pyridines; C504882:FYX-051; D014969:Xanthine Oxidase; D000077266:Moxifloxacin
ICH E14; Japanese; QT/QTc study; moxifloxacin; topiroxostat