Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Darpö, Börje; Garnett, Christine; Keirns, James J.; Stockbridge, Norman

doi:10.1007/s40264-015-0325-5

Cited by 50 publications

(58 citation statements)

References 25 publications

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“…The ICH E14 questions and answers (Q&A) were revised recently with harmonized guidance on how to use exposure-response modeling of QTc data (Q&A # 5.1) [31]. This ‘Early QT assessment’ could be used in lieu of thorough QT studies in some cases [32], which could potentially reduce drug development costs. However, this approach does not address the distinction between QTc prolonging drugs that selectively block the hERG potassium channel (high torsade risk) from QTc prolonging drugs that block inward currents in addition to the hERG potassium channel (low torsade risk) [9].…”

Section: Discussionmentioning

confidence: 99%

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

et al. 2016

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BackgroundDrugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the “CiPA” initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.Methods and ResultsIn this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).ConclusionsAnalysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.Trial RegistrationNCT02308748 and NCT01873950

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Section: Discussionmentioning

confidence: 99%

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

et al. 2016

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“…Using a highly automated approach performed with the COMPAS system (iCardiac Technologies Inc., Rochester, NY, USA), Darpo et al . (the IQ‐CSRC study) could demonstrate moxifloxacin‐induced QTcF prolongation using 10 replicate ECGs recorded in nine subjects receiving moxifloxacin and six receiving placebo in a parallel study (Darpo et al , ). In another simulation study, Ferber et al .…”

Section: Discussionmentioning

confidence: 99%

Detecting moxifloxacin‐induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach

Panicker

Karnad

Kadam

et al. 2016

British J Pharmacology

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Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects. EXPERIMENTAL APPROACHWe used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo. KEY RESULTSThe slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per μg -1 mL -1 ; at mean C max of 2.95 μg·mL À1 , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean C max exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%. CONCLUSIONS AND IMPLICATIONSOur study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability. AbbreviationsICH, International Conference on Harmonization; LOQ, limit of quantitation; SAD, single ascending dose; TQT, thorough QT/QTc

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“…Given that all 6 drugs were correctly identified, scientists and regulators involved in the study argued for the revision of ICH E14, which was implemented in December 2015 via the release of ICH E14 Q&A (R3) . The relevant question asked is “How can assessment of the concentration‐response relationship guide the interpretation of QTc data?” The opening paragraph of the detailed answer provided starts as follows: “Concentration‐response analysis, in which all available data across all doses are used to characterize the potential for a drug to influence QTc, can serve as an alternative to the by‐timepoint analysis or intersection‐union test as the primary basis for decisions to classify the risk of a drug.”…”

Section: An Example Of An Alternative Approaches To Qtc Risk Assessmementioning

confidence: 99%

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Turner

Rodríguez

Mantovani

et al. 2018

The Journal of Clinical Pharma

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Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

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Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Cited by 50 publications

References 25 publications

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Detecting moxifloxacin‐induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

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