Evaluation of the Potential QT Effect of Iptakalim Hydrochloride, an
Antihypertensive Drug, in Single- and Multiple-Ascending Dose Studies
Using Concentration-QTc Analysis
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.