Randomized, Controlled, Thorough QT/QTc Study Shows Absence of QT Prolongation with Luseogliflozin in Healthy Japanese Subjects

<div><p>Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.</p></div

Scatter plots of ΔΔQTcF and plasma concentrations of moxifloxacin.

<p>Abbreviation: r, correlation coefficient. Here, scatter plot represents correlation between ΔΔQTcF and plasma concentrations of Moxifloxacin 400 mg. Y-axis represents ΔΔQTcF (msec) and X-axis represents plasma concentration of Moxifloxacin (μg/mL).</p

Least-squares mean difference and 90% CI of ΔΔQTcF.

<p>Abbreviation: CI, confidence interval. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded for Luseogliflozin 5 mg, Luseogliflozin 20 mg, and Moxifloxacin 400 mg at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Y-axis represents ΔΔQTcF (msec) and X-axis represents post-dose time points (0.5, 1, 2, 3, 4, 6, 8, and 24 hours), when ECGs were recorded. Least-squares mean difference and 90% CI of ΔΔQTcF were represented by a dot and a vertical bar, respectively.</p

Plasma concentrations of moxifloxacin (mean + S.D.) Abbreviation: S.D., standard deviation.

<p>Plasma concentration of Moxifloxacin 400 mg was measured at 0.5, 1, 2, 3, 4, 6, 8, 24, and 48 hours post-dose. Y-axis represents plasma concentration of Moxifloxacin (μg/mL) and X-axis represents plasma concentration of Moxifloxacin measurements at 0.5, 1, 2, 3, 4, 6, 8, 24, and 48 hours post-dose. Here, mean and S.D. were represented by a dot and a vertical bar (upper bound), respectively.</p

Hysteresis plots of ΔΔQTcF and plasma concentrations of moxifloxacin.

<p>Here, Y-axis represents ΔΔQTcF (msec) and X-axis represents plasma concentration of unchanged Moxifloxacin (μg/mL). ΔΔQTcF (msec) was recorded at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose.</p

CONSORT 2010 Flow Diagram.

<p>Study design: A randomized, single dose, 4-period crossover study consisting of 4 treatment sequences.</p

Pharmacokinetic parameters of luseogliflozin and its metabolites (M2, M17) and moxifloxacin.

<p>*L 5 mg: Luseogliflozin 5mg, L 20 mg: Luseogliflozin 20 mg, M 400 mg: Moxifloxacin 400 mg</p><p>** Moxifloxacin unchanged compound (μg/mL)</p><p>*** Moxifloxacin unchanged compound (μg·hr/mL)</p><p>Pharmacokinetic parameters of luseogliflozin and its metabolites (M2, M17) and moxifloxacin.</p