Reducing QT liability and proarrhythmic risk in drug discovery and development

Valentin, Jean‐Pierre

doi:10.1111/j.1476-5381.2009.00547.x

Cited by 52 publications

(32 citation statements)

References 25 publications

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“…Torsades de Pointes is a rare, polymorphic, ventricular tachycardia associated with the prolongation of the QT interval [1]. Specifically, there is strong evidence that the prolongation effects of drug candidates on the QT interval form a risk factor for TdP and sudden cardiac death [2,3]. In view of this, the prolongation of the QT interval represented the reason for about one-third of drug withdrawals between 1990 and 2006, as reported in [4][5][6], involving different therapeutic areas [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…International Conference on Harmonization (ICH) S7A, S7B and E14 [12][13][14]) available so that only drugs with acceptable effects on the cardiovascular system get into the market [2]. For example, the guideline ICH E14 specifies that thorough QT (TQT) studies have to be performed in humans prior to market authorization, in order to assess the cardiovascular safety in man.…”

Section: Introductionmentioning

confidence: 99%

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Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

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Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

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“…1,5 hERG is mainly involved in repolarization current and its inhibition by drugs or compounds serves as a surrogate for QT (the time between the start of the Q wave and the end of the T wave) prolongation, which itself is a marker for Torsades de Pointes arrhythmia. 6 Most drugs withdrawn from the market appear to inhibit hERG channel activity by in vitro assays. 1,5 In addition to testing for hERG, lead compounds and drug candidates are also subjected to assays, which screen for direct damage to cardiomyocytes at the cellular or organellar level, such as mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Functional Cardiotoxicity Profiling and Screening Using the xCELLigence RTCA Cardio System

Xi¹,

Wang²,

Li³

et al. 2011

JALA: Journal of the Association for Laboratory Automation

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Cardiac safety testing of lead drug candidates is an important part of the drug discovery and development process. All new chemical entities need to be subjected to extensive preclinical assessment for cardiac liability, especially for a potentially fatal form of ventricular arrhythmia referred to as Torsades de Pointes. We have developed an innovative label-free, real-time system, the xCELLigence RTCA Cardio System, which is designed to monitor contractility of cardiomyocytes based on impedance measurement. The assay is performed using specially designed microtiter plates that are integrated with gold microelectrodes. The system was validated using mouse embryonic stem cell-derived cardiomyocytes, human-induced pluripotent stem cell-derived cardiomyocytes, and rat neonatal primary cardiomyocytes by applying a variety of tool compounds and drugs with known mechanisms of action. Our data show that the time resolution in the assay can provide important information about compound action. Furthermore, the impedance-based beating profile in response to compound treatment can provide mechanistic toxicity information regarding the target being modulated and may be able to flag pro-arrhythmic compounds. We believe the real-time and kinetic aspect of this technology combined with beat-to-beat measurement of cardiomyocyte contraction would make this instrument an important part of preclinical cardiac safety assessment.

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“…A number of drugs have had to undergo labelling revision or market withdrawal owing to postmarketing reports of sudden cardiac death linked to the development of torsades de pointes (TdP) [4][5][6][7][8][9][10]. It has been demonstrated that an excessive lengthening of cardiac repolarization (measured by QT interval prolongation) may induce these life-threatening ventricular tachyarrhythmias [11].…”

Section: Introductionmentioning

confidence: 99%

Translating QT interval prolongation from conscious dogs to humans

Dubois

Smania

et al. 2016

Brit J Clinical Pharma

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AIMIn spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. METHODSUsing estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between À0.98 ms μM -1 and 6.1 ms μM -1 in dogs and À10 ms μM -1 and 90 ms μM -1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. RESULTSFor compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = À1.709 + 11.6x; R 2 = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. CONCLUSIONSTogether with information about the expected therapeutic exposure, the evidence of a correlation between the compoundspecific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The use of model-based approaches for the screening of molecules in safety pharmacology is limited.• A previous investigation has shown the feasibility of characterizing pharmacokinetic-pharmacodynamic (PKPD) relationships as the basis for evaluating the risk of QT prolongation in dogs and humans. • The magnitude of drug effects on the QT/QTc interval varies across species as a result of the underlying differences in pharmacokinetics, pharmacodynamics and homeostasis. British Journal of Clinical Pharmacology• In spite of extensive screening procedures in early drug discovery, uncertainty remains about the propensity of nonantiarrhythmic drugs in prolonging the QT/QTc interval in humans. WHAT THIS STUDY ADDS• We showed evidence of the correlation between PKPD model parameters describing the drug-induced QT-prolonging effect in preclinical species and humans.• Drug-specific model parameter estimates obtained in dogs can be used to predict drug effects in humans, reducing the attrition due to false-positive and false-negative results during the screening of candidate molecules.• The interspecies difference in the slope of the correlation between drug concentrati...

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Reducing QT liability and proarrhythmic risk in drug discovery and development

Cited by 52 publications

References 25 publications

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Functional Cardiotoxicity Profiling and Screening Using the xCELLigence RTCA Cardio System

Translating QT interval prolongation from conscious dogs to humans

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