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 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.

Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open‐label randomized cross‐over study in healthy subjects

“…Regarding the safety results in this phase I study, zoliflodacin doses of 3 and 4 g were well‐tolerated in both the fed and fasted states. Both the number of subjects experiencing AEs and the types of AEs were in line with the most common TEAEs reported in previous phase I and II clinical trials of zoliflodacin 18,20,21 . All reported TEAEs were mild in severity.…”

“…Moreover, there was no notable change in QTcF values after dosing with zoliflodacin and the upper limit of the two-sided 90% CI did not exceed the regulatory threshold of 10 ms, in agreement with a TQT trial performed in a fasting state, with a 2 and 4 g dose of the granular formulation of zoliflodacin, which showed the absence of significative QT interval changes. 21 As exposure in the present study was higher in the fed state, results provided important additional data that was incorporated into a population PK model in advance of the clinical phase III study to ensure that any theoretical risk relating to QT interval changes was sufficiently minimized. Additionally, physiologically-based PK modeling efforts suggested a role for cytochrome P450 3A4 in the clearance of zoliflodacin.…”

“…Upon instruction to ship, one of the samples was shipped on dry ice for analysis, and the other remained at the site as backup. Plasma concentrations of zoliflodacin were determined at KCAS LLC using a vali—ted liquid chromatography with tandem mass spectrometry assay, as previously described 20,21 . The method involved the releasing of zoliflodacin and the added stable label internal standard (IS) zoliflodacin‐ 13 C 2 ‐ 15 N 2 (IS) from human plasma using protein precipitation.…”

“…Plasma concentrations of zoliflodacin were determined at KCAS LLC using a vali-ted liquid chromatography with tandem mass spectrometry assay, as previously described. 20,21 The method involved the releasing of zoliflodacin and the added stable label internal standard (IS) zoliflodacin-C 2 -15 N 2 (IS) from human plasma using protein precipitation. After protein precipitation, the supernatant was then subjected to reverse phase high performance liquid chromatography on a Gemini-NX C18 column and an AB Sciex API 5000 mass spectrometer was used for detection.…”

Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)

“…Patients should take at least 2 g of a single oral dose treatment of zoliflodacin to obtain effective N. gonorrhoeae suppression [ 136 ]. Additionally, studies revealed that the conventional therapeutic dose of 2 g does not induce cardiac arrhythmias and is well tolerated [ 137 ]. Although zoliflodacin maintains an excellent in vitro activity against clinical N. gonorrhoeae isolates, the rising potential to develop AMR led to further antibiotics research [ 138 ].…”