title: 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.).
authors.affiliation: RD Projects Clinical Platforms & Sciences, GSK, King of Prussia, Pennsylvania, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.affiliation: iCardiac Technologies, Rochester, New York, USA.
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: RD Projects Clinical Platforms & Sciences, GSK, Collegeville, Pennsylvania, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Tiffany
authors.affiliation: RD Infectious Disease, GSK, Collegeville, Pennsylvania, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dumont
authors.affiliation: Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden borje.darpo@telia.com.|iCardiac Technologies, Rochester, New York, USA.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
mesh_terms: D000073:Acenaphthenes / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000494:pharmacology*; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D055815:Young Adult
chemical_list: D000073:Acenaphthenes; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D006575:Heterocyclic Compounds, 3-Ring; C000612856:gepotidacin; D000077266:Moxifloxacin
keywords: QT prolongation; QTc; cardiac safety; healthy subjects; thorough QT study