Corresponding authors:
Hai Wang , Cardiovascular Drug Research Center, Thadweik Academy
of Medicine, 27 Tai Ping Road, Beijing 100853, China.
Tel: 86-10-66931557, Fax: 86-10-66931557.
E-mail:linchuang2218@126.com
Rui Wang , Center of Medicine Clinical Research, the PLA General
Hospital, 28 Fu Xing Road, Beijing 100853, China.
Tel: 86-10-66939409, Fax: 86-10-88214425.
E-mail:wangrui301@vip.sina.com
Yun Cai , Center of Medicine Clinical Research, the PLA General
Hospital, 28 Fu Xing Road, Beijing 100853, China.
Tel: 86-10-6693-6617, Fax: 86-10-8821-4425.
E-mail: caicai_hh@126.com
Abstract
Background: Cardiotoxicity has been one of the most common
causes for withdrawing drugs from the market, and its important
manifestation is the prolongation of QT interval. Iptakalim
hydrochloride (ITKL) is a selective ATP-sensitive potassium (KATP)
channel opener, it is crucial to assess the risk of cardiac
repolarization of ITKL in clinical trials. Objective:This
study was conducted to determine the effect of ITKL on corrected QT
(QTc) interval. Method: A randomized, double-blind,
placebo-controlled, single- and multi-dose regimen was carried out to
investigate the QTc and ITKL concentration correlation. ITKL was
administered at doses of 5 mg, 10mg, 15mg, and 20mg with single oral
administration and 10 mg, 20 mg with multiple oral administration, along
with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and
blood samples were collected on a preset time schedule. Result:The highest dose (20mg) of ITKL did not cause QTc prolongation with a
predicted ΔΔQTcF (Baseline and placebo-corrected QTc interval) effect
under geometric Cmax of 1.67 milliseconds, meeting the
criteria for negative effect on QT. The Exposure Response (ER) analysis
indicated the effect of the drug on ΔΔQTcF was relatively small.Conclusion: The upper bounds of the 90% confidence interval
(CI) of the model-predicted ΔΔQTcF at Cmax in all dose
groups were bellow 10ms, suggesting that ITKL did not prolong QT
interval.
Study registry identification number: The study was registered
at Chinese Clinical Trial Registry with registration number
ChiCTR1800014466.
Key words: Iptakalim, QT interval, Exposure response,
Cmax.