Dataset Information

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 (?QTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ?QTcF (??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. ??QTcF rapidly fell after the end of the infusion, with a mean ??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 ??QTcF, with a slope of 1.45 ms per ?g/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ??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 ?g/ml) and 1,800 mg (13 ?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 ?g/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.).

SUBMITTER: Hossain M

PROVIDER: S-EPMC5404516 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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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.

Hossain Mohammad M Zhou Meijian M Tiffany Courtney C Dumont Etienne E Darpo Borje B

Antimicrobial agents and chemotherapy 20170424 5

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-fro ...[more]

PMID: 28223381

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Project description:Tangzhiqing (TZQ), a Chinese herbal medicine, has been widely used to treat diabetes mellitus in China. TZQ works as a potential ?-glucosidase inhibitor to reduce the absorption of glucose from dietary carbohydrates. The main aim of this study was to investigate the postprandial glucose-lowering effect of TZQ on the common carbohydrates in healthy humans. Meanwhile, the possible types of the inhibited ?-glucosidase enzymes were predicted in this study. Glucose, sucrose, maltose, maltodextrin, and starch were chosen as investigated carbohydrates. The baseline incremental area under the curve (IAUC) and glycemic index (GI) values of the investigated carbohydrates were evaluated. Then, thirty-six subjects were randomly assigned to three groups to assess postprandial hypoglycemic effects of 3-, 6-, and 9-tablet TZQ. The subjects in each group were randomized to eight subgroups. An eight-period, eight-sequence, crossover design was performed to investigate the postprandial glucose-lowering effect of TZQ after drinking each carbohydrate. A significant decrease was observed on the postprandial glucose IAUCs (279.41?±?111.31 vs. 203.86?±?61.08) and GIs (124.91?±?48.54 vs. 91.69?±?27.47) of maltose after oral administration of 6-tablet TZQ, as well as IAUCs (145.05?±?55.01 vs. 110.23?±?57.03) and GIs (84.87?±?33.40 vs. 65.50?±?33.89) of sucrose after administration of 3-tablet TZQ. The glucose IAUCs (109.15?±?55.92 vs. 57.68?±?46.09) and GIs (49.09?±?25.15 vs. 25.94?±?20.73) of starch statistically reduced following the administration of 6-tablet TZQ. The lowering postprandial blood glucose effect of TZQ did not increase proportionally with increasing doses in humans. There were no significant changes in the glucose-lowering effect of glucose and maltodextrin after the administration of 3-, 6-, or 9-tablet TZQ, respectively. TZQ is a potential treatment for postprandial hyperglycemia, which can probably make ?-glucosidases inhibit maltase, sucrase, and ?-amylase in the digestive organs.

Dataset Information

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.

Publications

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.

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