A Phase I, Randomized, Double-Blinded, Placebo- and Moxifloxacin-Controlled, Four-Period Crossover Study To Evaluate the Effect of Gepotidacin on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram in Healthy Volunteers

Abstract

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, crossover thorough QT study in healthy subjects who were administered intravenous (i.v.) gepotidacin as a therapeutic (1,000-mg) dose and supratherapeutic (1,800-mg) dose, placebo, and 400 mg oral moxifloxacin in 4 separate treatment periods. Gepotidacin caused a mild effect on heart rate, with a largest placebo-corrected change-from-baseline heart rate of 7 and 10 beats per minute at the end of the 1,000-mg and 1,800-mg infusion, respectively. Gepotidacin caused an increase of change-from-baseline QTcF (ΔQTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ΔQTcF (ΔΔQTcF) was 12.1 ms (90% confidence interval [CI], 9.5 to 14.8) and 22.2 ms (90% CI, 19.6 to 24.9) after 1,000 mg and 1,800 mg, respectively. ΔΔQTcF rapidly fell after the end of the infusion, with a mean ΔΔQTcF of 6.1 ms 60 min after the 1,800-mg dose. Exposure-response analysis demonstrated a statistically significant positive relationship between gepotidacin plasma levels and ΔΔQTcF, with a slope of 1.45 ms per μg/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ΔΔQTcF can be predicted to be 11 and 20 ms at the observed mean peak plasma concentration after the infusion of gepotidacin at 1,000 mg (7 μg/ml) and 1,800 mg (13 μg/ml), respectively. In conclusion, gepotidacin caused QT prolongation in this thorough QT study, and a mean effect can be predicted to less than 15 ms at the highest expected plasma concentration, 9 μg/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.).

Keywords: QT prolongation; QTc; cardiac safety; healthy subjects; thorough QT study.

Copyright © 2017 Hossain et al.

Figures

FIG 1

Plasma concentration-time course after an intravenous infusion of 1,000 mg and 1,800 mg gepotidacin. Means ± SD are shown.

FIG 2

(A) Change-from-baseline heart rate (ΔHR) across treatments and time points. Least-squares means and 90% CI from the statistical modeling are shown. (B) Change-from-baseline QTcF (ΔQTcF) across treatments and time points. Least-squares means and 90% CI from the statistical modeling are shown.

FIG 3

Relationship between gepotidacin plasma concentrations and placebo-corrected change-from-baseline QTcF (ΔΔQTcF). (A) Scatter plot with all observed ΔΔQTcF/plasma concentration pairs and exposure-response model predicted effect (red line) with 90% CI. (B) Exposure-response model-predicted ΔΔQTcF (means and 90% CI) and observed ΔΔQTcF (means with 90% CI) within each gepotidacin plasma concentration decile.