A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization

Abstract

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

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Figures

FIG 1

Patient populations used for analysis. Safetya, all subjects who received at least 1 dose of study drug; PKb, all subjects who received at least 1 dose of study drug and had sufficient plasma concentration data to calculate the primary PK parameters; ECGc, all subjects who were randomly assigned, received at least 1 dose of study drug, and had at least 1 baseline (predose) ECG and 1 on-treatment (postdose) ECG within the same treatment period; PK/PDd, all subjects in the ECG population with time-matched plasma concentrations. ECG, electrocardiographic; PD, pharmacodynamic; PK, pharmacokinetic.

FIG 2

Placebo-adjusted change from the baseline QTcF (ms) versus time (electrocardiographic [PD] population). A mixed-effect general linear model (placebo adjusted and baseline corrected) was fitted for QTcF (ms) and included terms for treatment, gender, time, baseline value, time-by-treatment interaction, gender-by-baseline interaction of QTcF (ms), and time-by-treatment-by-gender interaction. Gender was a significant effect. Lower and upper bounds = lower and upper 2-sided 90% (1-sided 95%) model-based confidence limits. P values for gender effect were gender main effect = 0.6949, treatment-by-gender interaction = 0.2919, gender-by-baseline interaction = 0.5339, and treatment-by-gender-by-time interaction ≤ 0.0001. PD, pharmacodynamic; QTcF, corrected QT interval using Fridericia's formula.

FIG 3

QTcF placebo-corrected change from the baseline (ΔΔQTcF) versus delafloxacin plasma concentration (PK/PD population). The red line represents the mixed-effect regression prediction line. The gray line is a reference line at the predicted ΔΔQTcF interval for the supratherapeutic dose. These 2 lines cross at the mean Cmax value for the supratherapeutic dose (33.27 μg/ml). Conc., concentration; Cmax, maximum plasma concentration; PD, pharmacodynamic; PK, pharmacokinetic; QTcF, corrected QT interval using Fridericia's formula.