scholarly journals Clinical and Model‐Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study

2020 ◽  
Author(s):  
Joanna C. Masters ◽  
Naveed Shaik ◽  
Laure Mendes da Costa ◽  
Brian Hee ◽  
Robert R. LaBadie
Keyword(s):  
Cardiac Repolarization ◽  
Model Based ◽  
Thorough Qt Study

Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults

2021 ◽  
Author(s):  
Lori M. Newman ◽  
Martin Kankam ◽  
Aya Nakamura ◽  
Tom Conrad ◽  
John Mueller ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Cardiac Repolarization ◽  
Cardiac Safety ◽  
Double Blind ◽  
Thorough Qt Study ◽  
Regulatory Guidelines ◽  
Clinically Significant ◽  
The One ◽  
Global Threat

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.

scholarly journals A thorough QT study to assess the effects of tbo-filgrastim on cardiac repolarization in healthy subjects

2015 ◽  
pp. 2653 ◽  
Author(s):  
Liat Adar ◽  
Noa Avisar ◽  
Andreas Lammerich ◽  
Robert B. Kleiman ◽  
Ofer Spiegelstein
Keyword(s):  
Healthy Subjects ◽  
Cardiac Repolarization ◽  
Thorough Qt Study

Thorough QT study of the effect of fesoterodine on cardiac repolarization

2010 ◽  
Vol 48 (05) ◽  
pp. 309-318 ◽  
Author(s):  
B. Malhotra ◽  
N. Wood ◽  
R. Sachse ◽  
K. Gandelman
Keyword(s):  
Cardiac Repolarization ◽  
Thorough Qt Study

A Thorough QT Study of the Combination Glecaprevir + Pibrentasvir on Cardiac Repolarization in Healthy Subjects

2020 ◽  
Vol 42 (7) ◽  
pp. 1317-1329
Author(s):  
Rajneet K. Oberoi ◽  
Weihan Zhao ◽  
Matthew Rosebraugh ◽  
Federico Mensa ◽  
Haoyu Wang ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Cardiac Repolarization ◽  
Thorough Qt Study

Evaluation of the Effect of Arbaclofen Placarbil, a Novel Transported Prodrug of R-Baclofen, on Cardiac Repolarization in a Thorough QT Study in Healthy Subjects

2009 ◽  
Vol 104 ◽  
pp. S17-S18
Author(s):  
Dan Chen ◽  
Ritu Lal ◽  
Jacob F. Huff ◽  
Juthamas Sukbuntherng ◽  
Wendy Luo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Cardiac Repolarization ◽  
Thorough Qt Study

Effects of Standard and Supratherapeutic Doses of Nelfinavir on Cardiac Repolarization: A Thorough QT Study

2009 ◽  
Vol 49 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Bharat Damle ◽  
Cecilia Fosser ◽  
Kaori Ito ◽  
Anh Tran ◽  
Pamela Clax ◽  
...  
Keyword(s):  
Cardiac Repolarization ◽  
Thorough Qt Study

scholarly journals The effect of the glucosylceramide synthase inhibitor lucerastat on cardiac repolarization: results from a thorough QT study in healthy subjects

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Markus S. Mueller ◽  
Patricia N. Sidharta ◽  
Christine Voors-Pette ◽  
Borje Darpo ◽  
Hongqi Xue ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Plasma Concentrations ◽  
Published Data ◽  
Cardiac Repolarization ◽  
Qtc Interval ◽  
Glucosylceramide Synthase ◽  
Assay Sensitivity ◽  
Benefit Risk Assessment ◽  
Thorough Qt Study ◽  
Synthase Inhibitor

Abstract Background Fabry disease is a rare inherited glycosphingolipid storage disorder caused by deleterious mutations in the GLA gene coding for the lysosomal enzyme α-galactosidase A. The glucosylceramide synthase inhibitor lucerastat is an iminosugar with potential to provide oral substrate reduction therapy in Fabry disease, regardless of the patient´s underlying mutation. Since lucerastat exhibits systemic exposure and many patients with Fabry disease suffer from rhythm and conduction abnormalities its effects on cardiac repolarization were evaluated in a thorough QT study. Methods In Part A of this randomized, double-blind, placebo-controlled phase 1 study, single oral doses of 2000 and 4000 mg lucerastat were investigated to determine the supratherapeutic dose for Part B. The latter was a four-way crossover study to demonstrate that lucerastat at single oral therapeutic and supratherapeutic doses had no effect on the QTc interval > 10 ms using concentration-QTc modeling as primary analysis. The primary ECG endpoint was placebo-corrected change-from-baseline (ΔΔ) in Fridericia-corrected QTc (ΔΔQTcF). Open-label moxifloxacin served as positive control. Results The effect of lucerastat on ΔΔQTcF was predicted as 0.39 ms (90% confidence interval [CI] − 0.13 to 0.90) and 1.69 ms (90% CI 0.33–3.05) at lucerastat peak plasma concentration after dosing with 1000 mg (5.2 µg/mL) and 4000 mg (24.3 µg/mL), respectively. A QTcF effect > 10 ms was excluded up to lucerastat plasma concentrations of approximately 34.0 µg/mL. Lucerastat did not exert an effect on other ECG parameters. Across doses, absorption of lucerastat was rapid, its elimination half-life ranged from 8.0 to 10.0 h, and the pharmacokinetics (PK) of lucerastat were dose-proportional. Moxifloxacin PK were in line with published data and assay sensitivity was demonstrated by the moxifloxacin QTc response. Lucerastat was safe and well tolerated. Conclusions Lucerastat up to a dose of 4000 mg has no clinically relevant liability to prolong the QT interval or any clinically relevant effect on other ECG parameters. This will be an important factor in the overall benefit-risk assessment of lucerastat in the potential treatment of Fabry disease. Trial registration The study was registered with the ClinicalTrials.gov identifier NCT03832452 (February 6th, 2019, https://clinicaltrials.gov/ct2/show/NCT03832452) and the EudraCT number 2018-004546-42 (December 17th, 2018).

scholarly journals A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

2020 ◽  
Vol 9 (3) ◽  
pp. 307-320
Author(s):  
Richat Abbas ◽  
Steve Riley ◽  
Robert R. LaBadie ◽  
Mary Bachinsky ◽  
Phillip B. Chappell ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Cardiac Repolarization ◽  
Supratherapeutic Dose ◽  
Thorough Qt Study

Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers

2011 ◽  
Vol 27 (7) ◽  
pp. 1453-1463 ◽  
Author(s):  
Y.-L. He ◽  
Y. Zhang ◽  
D. Serra ◽  
Y. Wang ◽  
M. Ligueros-Saylan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Cardiac Repolarization ◽  
Thorough Qt Study

Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis

2021 ◽  
Author(s):  
Uta Schilling ◽  
Andrea Henrich ◽  
Clemens Muehlan ◽  
Andreas Krause ◽  
Jasper Dingemanse ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cardiac Repolarization ◽  
Thorough Qt Study
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