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Evaluation of the Potential QT Effect of Iptakalim Hydrochloride, an Antihypertensive Drug, in Single- and Multiple-Ascending Dose Studies Using Concentration-QTc Analysis
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  • Nan Bai,
  • Jin Wang,
  • Haoyue Che,
  • Hai Wang,
  • Rui Wang,
  • Yun Cai
Nan Bai
Chinese PLA General Hospital
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Jin Wang
Chinese PLA General Hospital
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Haoyue Che
Chinese PLA General Hospital
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Hai Wang
Thadweik Academy of Medicine
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Yun Cai
Chinese PLA General Hospital
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Peer review status:UNDER REVIEW

03 Jun 2020Submitted to British Journal of Clinical Pharmacology
11 Jun 2020Assigned to Editor
11 Jun 2020Submission Checks Completed
06 Jul 2020Reviewer(s) Assigned


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.