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 (⌬⌬QTcF) 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 ⌬⌬QTcF 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 ⌬⌬QTcF. 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. Delafloxacin (RX-3341, ABT-492, and WQ-3034) is an anionic investigational fluoroquinolone antibiotic, currently in phase III development for the treatment of acute bacterial skin and skin structure infections (ABSSSI) based on its activity against Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus, Gram-negative microorganisms, and anaerobes (1). Pharmacokinetic (PK) studies have shown that the increases in the maximum plasma concentration (C max ) and total exposure (area under the concentration-time curve [AUC]) are dose proportional and greater than dose proportional, respectively, with a single intravenous (i.v.) dose of 300 to 1,200 mg in healthy volunteers (2). Both i.v. and oral formulations are expected to be available, allowing i.v.-to-oral "step-down" therapy in the appropriate patient populations. The proposed dose for the treatment of ABSSSI is 300 mg administered i.v. or 450 mg administered orally (p.o.) twice daily (BID).QT interval prolongation caused by the inhibition of potassium channels encoded by the HERG gene has been described for a variety of drug classes, including the fluoroquinolone antibiotics (3, 4). QT prolongation is associated with an increased risk of life-threatening cardiac arrhythmias, most typically torsades de pointes (TdP). The degree to which the fluoroquinolones block the cardiac potassium channels, thereby prolonging the QT interval, varies by agent (5, 6). In ...

What Is Old Is New Again: Delafloxacin, a Modern Fluoroquinolone

“…Safety data from phase 1, 2, and 3 clinical trials suggest that the adverse effect profile of delafloxacin is similar to that of other fluoroquinolones, with the most common being gastrointestinal. However, QTc prolongation and phototoxicity do not seem to be of concern with delafloxacin . In a phase 1 study, IV delafloxacin was administered via a single‐ascending dose, ranging from 300 mg to 1200 mg .…”

“…QTc prolongation was assessed in a phase 1, four‐period crossover study comparing IV delafloxacin at therapeutic (300 mg) and supratherapeutic doses (900 mg) to moxifloxacin (400 mg) . Delafloxacin did not produce any clinically relevant increases in QTc levels, while moxifloxacin produced predicted increases in QTc levels.…”

“…However, QTc prolongation and phototoxicity do not seem to be of concern with delafloxacin. 51,52 In a phase 1 study, IV delafloxacin was administered via a single-ascending dose, ranging from 300 mg to 1200 mg. 53 At higher doses (≥ 750 mg), patients exhibited a higher percentage of adverse reactions, while doses of 300 mg were equivalent to that of the placebo group. This same study enrolled 56 healthy subjects in an open-label, randomized, two-period, two-sequence crossover study where patients were randomized to either a single oral dose (450 mg) or IV dose (300 mg) of delafloxacin.…”

Advances in the medical management of skin and soft tissue infections

“…Notably, no QTc interval prolongation occurred, which differentiates delafloxacin from other fluoroquinolones. 87 Iclaprim Pharmacology Iclaprim, a diaminopyrimidine derivative, is a bacterial dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase leads to a shortage of nucleosides, interfering with DNA synthesis and leading to cell death.…”

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

“…Similarly, no adverse events at the level of the tendons, muscles, joints, nerves, and central nervous system have been recorded. In a randomized study conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval, the absence of a clinically meaningful increase in the QTc interval was demonstrated [35]. In a phase I study, no clinically significant phototoxicity potential was assessed for delafloxacin compared to lomefloxacin, at any wavelength tested [36] …”