Dataset Information

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

ABSTRACT: 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 at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, and moxifloxacin at 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 h after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the predose 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 to 4 h after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, electrocardiogram (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 that zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03613649.).

SUBMITTER: Newman LM

PROVIDER: S-EPMC8597722 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Newman Lori M LM Kankam Martin M Nakamura Aya A Conrad Tom T Mueller John J O'Donnell John J Osborn Blaire L BL Gu Kenan K Saviolakis George A GA

Antimicrobial agents and chemotherapy 20211004 12

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 at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, a ...[more]

PMID: 34606332

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Project description:BackgroundFabry 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.MethodsIn 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.ResultsThe 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.ConclusionsLucerastat 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).

Dataset Information

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

Publications

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

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