Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

Gintant, Gary A.; Su, Zhi; Martin, Ruth L.; Cox, Bryan F.

doi:10.1080/01926230500431376

Cited by 81 publications

(58 citation statements)

References 87 publications

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“…Since hERG channel inhibition is the main mechanism that underlies the acquired long QT syndrome and TdP, hERG blocking potency is a surrogate marker for proarrhythmic properties of drugs or drug candidates. IC 50 for hERG channels inhibition assays is considered a primary test for cardiac safety of drug candidates that can support go/no go decision making at early development stages (De Ponti et al, 2000;EMEA, 1997;Gintant et al, 2006;Woosley and Sale, 1993).…”

Section: Introduction Physiological Aspects Of the Drug-induced Cardimentioning

confidence: 99%

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Polak¹,

Wiśniowska

Brandys³

2008

J of Applied Toxicology

100

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The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug-hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC(50)) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC(50) values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC(50) data available in accessible scientific literature to provide a high-quality data set for further studies.

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Section: Introduction Physiological Aspects Of the Drug-induced Cardimentioning

confidence: 99%

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Polak¹,

Wiśniowska

Brandys³

2008

J of Applied Toxicology

100

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“…However, the link between QT interval prolongation and TdP appears multifaceted and is influenced by a number of underlying factors including age, gender, underlying disease state, electrolyte imbalance, concomitant medication, and more. 1,2 Although the majority of compounds that can induce TdP are known to inhibit cardiac potassium channels encoded by human-ether-à-go-go Related Gene (hERG), [3][4][5] block of ionic current (I hERG ) carried by recombinant hERG channels alone is not always predictive of delayed repolarization or proarrhythmic risks. For example, the L-type calcium channel blocker verapamil is a potent blocker of hERG current 6 but does not prolong the QT interval or pose a risk of TdP.…”

Section: Introductionmentioning

confidence: 99%

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

et al. 2016

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For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a publicprivate collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell-derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.

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“…This result is most easily explained by the fact that verapamil also blocks the L-type (inward) cardiac Ca 2+ current, likely offsetting the reduced outward K + current due to hERG block. The simultaneous effects of a drug on multiple ion channels (termed multichannel block) are best appreciated when comparing ion channel assay results with in vitro repolarization studies [3,45,46]. Indeed, one may consider the cardiac action potential as a collection of simultaneous (and possibly interdependent) ion channel assays with different sensitivities to block different channels.…”

Section: Timing Of Cardiac Ion Channel Screening In Drugmentioning

confidence: 99%

“…This allows for comparison with in vivo effects of drugs and calculation of therapeutic margins [3,14]. The IC 50 value for hERG blockade is the concentration at which hERG current (usually peak tail) is inhibited by 50% and is obtained by fitting the concentration-response relationship to the Hill equation: typically 3-4 concentrations should be tested that encompass a reasonable concentration range.…”

Section: Traditional Approaches To Measuring Drug Effects On Hergmentioning

confidence: 99%

“…In this way, drugeffects are defined based on changes in membrane currents affected in response to imposed voltage-clamp protocols. Conventional (or so-called manual patch-clamp (MPC)) techniques are considered as the "gold standard" electrophysiological assay for evaluating drug effects on voltage-gated channels [2][3][4][5]. MPC technique can be applied to many electrically excitable cells, including cells either transiently or stably expressing the hERG channel and native cardiac myocytes.…”

Section: Electrophysiological Screens For Drug Effects On Herg/i Kr Cmentioning

confidence: 99%

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Preclinical Drug Safety and Cardiac Ion Channel Screening

Gintant

2011

Heart Rate and Rhythm

Self Cite

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A new chemical entity must demonstrate efficacy and safety in order to be considered a successful therapeutic agent. Towards that goal, it is best to discover drugs demonstrating a wide concentration range between (lower) preclinical efficacious plasma concentrations and (higher) plasma concentrations eliciting preclinical off-target adverse effects. Drugs possessing such characteristics provide greater flexibility in clinical trials and explorations into alternative indications. Thus, preclinical studies related to both efficacy and safety must be considered equally important during drug discovery efforts. Cardiac safety plays a key role in defining the safety of novel therapeutics, and defining a drug's therapeutic window/safety margin.Much emphasis has been placed in the past decade on detecting (and avoiding) the ability of non-cardiovascular drugs to delay or alter ventricular repolarization (acquired long QT syndrome [1]). This focus arises in part from the association of delayed repolarization to the rare but potentially life-threatening arrhythmia torsades de pointes. As torsades is a rare event, surrogate markers are employed to detect and avoid this potential proarrhythmic risk. Preclinically, the most recognized in vitro marker for delayed repolarization is drug block of I Kr (an outward repolarizing current that initiates and defines terminal ventricular repolarization). In humans, the a-subunit of the I Kr channel is encoded by the human ether-a-go-go related gene (hERG) gene. Block of hERG/I Kr along with prolongation of the QT interval (an interval on the ECG that generally represents the onset of ventricular depolarization and the termination of ventricular repolarization) form the presentday cornerstone for cardiac electrophysiologic safety testing. Due to the importance of testing hERG current as a surrogate marker of proarrhythmia, great strides have been made in developing and streamlining testing protocols/procedures to evaluate

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Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

Cited by 81 publications

References 87 publications

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

Preclinical Drug Safety and Cardiac Ion Channel Screening

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