Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative

Huang, Hai; Pugsley, Michael K.; Fermini, Bernard; Curtis, Michael J.; Koerner, John; Accardi, Michael V.; Authier, Simon

doi:10.1016/j.vascn.2017.04.002

Cited by 61 publications

(31 citation statements)

References 140 publications

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“…The effect of drugs on cardiac repolarization-through assessment of the QT interval of the electrocardiogram (ECG)-is an important tool in the assessment of the propensity of novel medical products to induce arrhythmias, which has been a major cause of drug withdrawals from the market or clinical development. [1][2][3][4] Clinical and pharmacological studies have indicated that the vulnerability to induced arrhythmias varies throughout the day. 5,6 Regulation of cardiac function by diurnal factors enables efficient coupling of physiological response to anticipated environmental demand.…”

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confidence: 99%

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Täubel

Ferber

Fernandes

et al. 2018

The Journal of Clinical Pharma

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Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.

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confidence: 99%

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Täubel

Ferber

Fernandes

et al. 2018

The Journal of Clinical Pharma

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“…These molecular determinants highlight a complexity that may guide future work on open state block specificity. In addition, our results exemplify the need to use CiPA guidelines when assessing clinically promising drugs [19].…”

Section: Introductionmentioning

confidence: 62%

“…As a result, the re-classification of R -roscovitine as a Class VI antiarrhythmic agent was recently proposed due to its selective non-peak block of the late I Ca,L current, which likely averts cardiac arrhythmias [59,60]. Such compensatory mechanisms are now sought after, with the CiPA guidelines recommending that all drugs be screened not only against hERG but also for L-type calcium channel and sodium channel block [19]. Thus, revisiting drugs that were deemed clinically unsafe due to hERG block, but exhibit compensatory drug actions, may yield new pharmaceutical therapeutics and will support the CiPA initiative on proarrhythmia risk assessments.…”

Section: Discussionmentioning

confidence: 99%

“…It is estimated that 1 out of every 5 intensive care unit (ICU) patients experiences a form of cardiac arrhythmia that is highly influenced by QT-prolonging medications [14–16]. Because of the dangerous side effects, pharmaceuticals have been routinely screened for hERG interaction [17,18], which has unfortunately led to the loss of promising drugs that may not have posed a clinical proarrhythmic risk [19]. Interestingly, many clinically-safe drugs turned out to inhibit hERG, which prompted CiPA guidelines recommending the re-evaluation of previously discarded, yet promising drugs; the features of such drugs are under investigation [19].…”

Section: Introductionmentioning

confidence: 99%

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The molecular determinants of R-roscovitine block of hERG channels

Cernuda

Fernandes

Allam

et al. 2019

Preprint

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14Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that 15 conducts the delayed rectifier potassium current (I Kr ) during the repolarization phase of cardiac 16 action potentials. hERG channels have a larger pore than other K + channels and can trap many 17 unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine, a cyclin-dependent 18 kinase (CDK) inhibitor that also inhibits L-type calcium channels, inhibits open hERG channels 19 but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus 20 oocytes expressing wild-type (WT) or mutant (T623A, S624A, Y652A, F656A) hERG channels 21 demonstrated that, compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 µM R-22 roscovitine was ~ 48 %, 29 %, and 73 % weaker, respectively. In contrast, S624A hERG was 23 inhibited more potently than WT hERG, with an ~ 34 % stronger inhibition. These findings were 24 further supported by the IC 50 values, which were increased for T623A, Y652A and F656A (by 25~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data 26 suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 27 may not be. This relatively unique feature, coupled with R-roscovitine's tolerance in clinical 28 trials, could guide future drug screens. We discuss our findings and how they lend support for the 29 recent Comprehensive In Vitro Proarrhythmia Assay (CiPA) guidelines on the re-evaluation of 30 potentially useful drugs that had failed testing due to unintended interactions with hERG. 31 32 Introduction 33 Human ether-à-go-go-related gene, or hERG [Kv11.1], is a voltage-gated potassium 34 channel critical for nerve and cardiac function [1,2]. In the heart, hERG channels initially open 3 35 during the depolarization phase of the cardiac action potential (cAP) but immediately inactivate. 36 Upon cAP repolarization, hERG channels de-inactivate and reopen, which allows the ensuing 37 large K + efflux to speed cAP repolarization [1], limit cardiac excitability, and maintain normal 38 QT intervals [3]. Consequently, mutations in hERG are one of the leading causes of congenital 39 long QT syndrome (cLQTS), with a neonatal incidence rate of up to 1 in 2,500 [4]; abnormal 40 cardiac phenotypes are usually triggered during exercise, arousal, or rest [5].41 hERG channels are tetrameric proteins, with each monomer consisting of six 42 transmembrane alpha helices (S1-S6) and cytoplasmic amino and carboxy termini [6]. Similar to 43 other voltage-gated channels, S1-S4 is considered the primary voltage-sensing region, with S4 44 containing positively-charged residues that move slowly outward to induce the characteristically 45 slow activation kinetics of hERG [7,8]. The four S5 and S6 helices and their intervening 46 sections, including the P-loops and P-helices, form the pore and selectivity filter of the channel 47 [9,10]. The pore is thought to have a region between the pore helix and the S6 segments that may 48 provide p...

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“…Additional references are provided. [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82]…”

Section: The Comprehensive In Vitro Proarrhythmia Assaymentioning

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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Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative

Cited by 61 publications

References 140 publications

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

The molecular determinants of R-roscovitine block of hERG channels

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

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