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

作者：Hossain Mohammad; Zhou Meijian; Tiffany Courtney; Dumont Etienne; Darpo Borje^*

来源：Antimicrobial Agents and Chemotherapy, 2017, 61(5): e02385-16.

DOI：10.1128/AAC.02385-16

• QT prolongation
• QTc
• cardiac safety
• healthy subjects
• thorough QT study

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 (Delta QTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected Delta QTcF (Delta Delta QTcF) 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. Delta Delta QTcF rapidly fell after the end of the infusion, with a mean Delta Delta QTcF 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 Delta Delta QTcF, with a slope of 1.45 ms per mu g/ml (90% CI, 1.30 to 1.61). Using this model, the effect on Delta Delta QTcF 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 mu g/ml) and 1,800 mg (13 mu g/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 mu g/ml.

• 出版日期2017-5