ICH E14 Q&amp;A(R2) document: commentary on the further updated recommendations on thorough QT studies

Shah, Rajiv; Morganroth, Joel; Kleiman, Robert B.

doi:10.1111/bcp.12477

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…The validity of the sample size selected and the methodology used was demonstrated by the effects of the oral moxifloxacin 400 mg dose (positive control). The effects of moxifloxacin on QTc interval are well characterized and were detected as expected in this study [ 15 ]. Assay sensitivity was demonstrated by moxifloxacin prolonging QTcI.…”

Section: Discussionsupporting

confidence: 79%

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Cassella¹,

Spyker²,

Yeung³

2015

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Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. Results: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. Conclusions: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

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Section: Discussionsupporting

confidence: 79%

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Cassella¹,

Spyker²,

Yeung³

2015

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“…Given the vast experience with the use of moxifloxacin as the active control, our study also supports an earlier recommendation that a single oral dose of 400 mg moxifloxacin should be the standard positive control unless there are reasons not to use it [37]. Furthermore, our study found that correction of the measured QT interval for heart rate by Fridericia's formula was superior to an individually-derived correction formula.…”

Section: Qt C F or Qt C I Correctionsupporting

confidence: 85%

Moxifloxacin‐induced QT_c interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study

Morganroth

Wang

Thorn

et al. 2015

Brit J Clinical Pharma

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AIMWe investigated whether moxifloxacin-induced QT c prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODSA two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QT c interval from baseline (ΔΔQT c F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQT c F for each population, and the difference between the two, were calculated at a geometric mean C max of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQT c F was contained within À5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTSThere were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin C max (3.27 ± 0.6 vs. 2.98 ± 0.7 μg ml -1 ), ΔΔQT c F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at C max of 3.07 μg ml ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per μg ml -1

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“…Because the true value of the ΔΔQTc is unknown, the best estimate of the ΔΔQTc for each formula was considered to be the mean ΔΔQTc of 18 ECG replicates. The difference between the mean ΔΔQTc of each replicate count (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and the mean ΔΔQTc of 18 ECG replicates was calculated, and this results in a Δ 18 replicates Δ placebo Δ baseline QTc (ΔΔΔQTc). The results of this analysis were displayed as a heat map ( Fig.…”

Section: δ Placebo δ Baseline Qtc Calculationmentioning

confidence: 99%

“…8,10 However, several elements in current practice to measure a compound's QT prolonging effect are not underpinned by peerreviewed scientific data. This includes the number of ECG replicates that are recorded, which is arbitrarily set at 3 or more by the regulators, 4,11 and the QT correction formula that is deployed. 12,13 Therefore, we performed an analysis on ECG recordings obtained in a placebo-controlled phase I single ascending dose trial with a compound that prolonged the QT interval.…”

Section: Introductionmentioning

confidence: 99%

Number of ECG Replicates and QT Correction Formula Influences the Estimated QT Prolonging Effect of a Drug

Wall

Gal

Kemme

et al. 2019

Journal of Cardiovascular Pharmacology

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Introduction: The present analysis addressed the effect of the number of ECG replicates extracted from a continuous ECG on estimated QT interval prolongation for different QT correction formulas. Methods: For 100 healthy volunteers, who received a compound prolonging the QT interval, 18 ECG replicates within a 3-minute window were extracted from 12-lead Holter ECGs. Ten QT correction formulas were deployed, and the QTc interval was controlled for baseline and placebo and averaged per dose level. Results: The mean prolongation difference was >4 ms for single and >2 ms for triplicate ECG measurements compared with the 18 ECG replicate mean values. The difference was <0.5 ms after 14 replicates. By contrast, concentration–effect analysis was independent of replicate count and also of the QT correction formula. Conclusion: The number of ECG replicates impacted the estimated QT interval prolongation for all deployed QT correction formulas. However, concentration–effect analysis was independent of both the replicate number and correction formula.

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ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

Cited by 11 publications

References 25 publications

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Moxifloxacin‐induced QT_c interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study

Number of ECG Replicates and QT Correction Formula Influences the Estimated QT Prolonging Effect of a Drug

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ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

Cited by 11 publications

References 25 publications

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Moxifloxacin‐induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study

Number of ECG Replicates and QT Correction Formula Influences the Estimated QT Prolonging Effect of a Drug

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Moxifloxacin‐induced QT_c interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study