Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review

Garnett, Christine; Beasley, Nhi; Bhattaram, Venkatesh Atul; Jadhav, Pravin; Madabushi, Rajanikanth; Stockbridge, Norman; Tornøe, Christoffer Wenzel; Wang, Yaning; Zhu, Hao; Gobburu, Jogarao

doi:10.1177/0091270007307881

Cited by 210 publications

(230 citation statements)

References 26 publications

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“…Individual median-centred baseline values were obtained by subtracting each baseline QTcI value from this median value. Using these models, regression lines for concentration vs. ΔQTcI and their 90% two-sided confidence limits were plotted for males and females [13]. To compare the regression lines in males and females, a hypothesis of coincidence, that is, the relationships between ΔQTc and plasma concentration in males and females were evaluated by testing gender and gender × concentration interaction effects at a twosided alpha of 0.05.…”

Section: Discussionmentioning

confidence: 99%

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Darpö

Karnad

Badilini³

et al. 2014

Br J Clin Pharmacol

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AIMTo study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODSContinuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTSRac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml −1 (range 1.1-2.8) vs. 1.4 μg ml −1 (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTcI relationship was steeper in women (30 ms per μg ml −1 vs. 23 ms per μg ml −1 in men; P = 0.0135). CONCLUSIONSThe study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Women have a longer QTc interval and an increased risk for pro-arrhythmias caused by drug-induced delayed cardiac repolarization.• This increased risk cannot be explained by gender differences in plasma concentration of the drug.• This study evaluated the QTc-plasma concentration relationship after dosing of rac-sotalol in men and women. WHAT THIS STUDY ADDS• When given a therapeutic dose of rac-sotalol, the slope of the relationship between rac-sotalol concentration and change in QTc interval was steeper in women.• This indicates a greater sensitivity in women as compared with men for rac-sotalol-induced QT prolongation, which may contribute to the greater pro-arrhythmic risk in women.

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Section: Discussionmentioning

confidence: 99%

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Darpö

Karnad

Badilini³

et al. 2014

Br J Clin Pharmacol

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“…Moxifloxacin at 400 mg was included as a positive control to validate the sensitivity of the assay to detect small increases in the QTcF duration from the baseline based on studies showing mean increases in QTc of 6 ms using a time-averaged analysis (12) and of 10 to 15 ms using a timematched analysis (13). Assay sensitivity was established based on baselinecorrected change in QTcF at 1, 1.5, 2, 3, and 4 h after ingestion, which correspond with the times during which the plasma concentration is highest (14,15).…”

Section: Methodsmentioning

confidence: 99%

A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

Litwin

Benedict

Thorn

et al. 2015

Antimicrob Agents Chemother

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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 ...

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“…It is crucial that experimental conditions be uniform across all treatment groups to provide assurance that effects observed in both the placebo and positive control arms occurred under the same conditions as for the investigational medicinal product arms. The relationship between drug concentration and QT/ QTc effects is routinely assessed during regulatory reviews [3][4][5]. The moxifloxacin effect on QT was previously satisfactorily described with a direct and proportional concentration effect [6].…”

Section: Introductionmentioning

confidence: 99%

Moxifloxacin versus placebo modeling of the QT interval

Urien

2012

J Pharmacokinet Pharmacodyn

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The objectives were to develop a population model for placebo-corrected moxifloxacin QT interval in healthy subjects using non-linear mixed effects modeling and to examine effect of covariates on the observed QT. Based on the parameters of interest, optimizations of observation times and number of subjects were proposed. A pool of four thorough QT studies was used, representing 99 subjects receiving placebo and moxifloxacin. The data was modeled using Monolix. The placebo effect on QT was satisfactorily described using a 2-oscillator model. It reflected the circadian rhythm variability which is taken into account when assessing the time-matched mean difference on QT between treatment and baseline. Based on this model, the moxifloxacin effect on QT was satisfactorily described by the same equation with the adjunct of a direct and proportional drug concentration-effect. The Emax model provided the best description of the effect. The unique covariate was gender for both baseline QTc and individual heart rate correction factor. The present design included up to 16 observations for pharmacodynamics. Using this model, 9 observation times for pharmacodynamics provided satisfactory estimates for the parameters of interest (Emax). With 15% precision limit on Emax, 60 subjects was optimal. The simultaneous placebo-moxifloxacin QT model proposed is an interesting alternative to the ICH E14 guideline in assessing QT prolongation effect. This approach provides accurate information over a range of concentrations using different relationships (slope or Emax models) to quantify the drug-response relationship versus placebo. This allowed optimizing the observation times and number of subjects.

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Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review

Cited by 210 publications

References 26 publications

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

Moxifloxacin versus placebo modeling of the QT interval

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Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review

Cited by 210 publications

References 26 publications

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

Moxifloxacin versus placebo modeling of the QT interval

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Product

Resources

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Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol