Understanding drug-induced torsades de pointes: a genetic stance

Drugs may produce a variety of arrhythmias, but drug-induced QT prolongation and the risk of the polymorphic ventricular tachycardia torsades de pointes (drug-induced long QT syndrome) has garnered the most attention. The wide array of drugs with potential for QT prolongation, the correspondingly large number of patients exposed to such drugs, the difficulty in predicting an individual's risk, and the potentially fatal outcome, make drug-induced long QT syndrome an important public health problem for clinicians, researchers, drug development programs, and regulatory agencies. This review focuses on the genetic risk factors and mechanisms underlying QT prolongation and proarrhythmia. The post-genomic era hints at an improved understanding (and prediction) of how the gene-environment interaction produces this particular adverse drug response.     

Drug induced shortening of the QT/QTc interval: An emerging safety issue warranting further modelling and evaluation in drug research and development?

IntroductionA session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh.MethodsThe session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing “for” and “against” QT/QTc shortening being a safety issue and a panel discussion with the audience.ResultsCompared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future.DiscussionCurrently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.     

An update on risk factors for drug-induced arrhythmias

A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ‘‘effect amplifiers’’ which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, T_peak–T_end/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias.     

Drug induced QT prolongation: lessons from congenital and acquired long QT syndromes

Recent developments regarding the underlying genetic and intracardiac ion channel causes of congenital long QT syndrome have shed new light in the area of repolarization disorders and their resultant cardiac arrhythmias. Drug induced or acquired QT prolongation often represents a latent form of congenital long QT syndrome, though the genetic basis of this has not been elucidated in the majority of cases. Understanding this has lead to a new concept of repolarization reserve, a measure of inherent susceptibility to repolarization-mediated arrhythmias. The majority of pharmacologic agents that cause significant QT prolongation have potassium channel blocking characteristics, predominantly affecting the rapidly activating current I(Kr). The list of agents known to affect I(Kr)continues to grow, best monitored through several websites that collate reports of drug-induced QT prolongation and arrhythmias. Discontinuation of the offending agent and supportive care are often all that is necessary when clinical arrhythmias arise.     

Models for profiling the potential QT prolongation risk of drugs

The appearance of QT prolongation and arrhythmic events associated with a compound undergoing clinical trials can greatly hamper drug development programs. Assessing the risk of a compound during preclinical studies to cause this cardiotoxicity is thus critically important to the pharmaceutical industry. A wide variety of preclinical approaches exist to evaluate potential QT issues, including in vitro, in vivo and in silico (i.e., computer simulation) methods. We present an evaluation of recent reports implementing these techniques, with an emphasis on the linkage between drug-induced cardiac action potential changes and QT prolongation both in vitro and in silico. We conclude with a strategy that integrates in silico modeling with in vitro and in vivo experimentation to create a compelling package for assessing potential proarrhythmic risk of a compound.     

Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes

Over the past several years a multitude of new pharmaceutical agents have been released to the market. Several of them were withdrawn altogether or their use severely restricted to certain indications due to unexpected adverse events, including fatalities. Progress in developing new compounds clearly has surpassed our technology, in some cases, to measure and predict certain toxicities. Prolongation of the QT interval, which may lead to potentially life-threatening ventricular arrhythmias such as torsades de pointes, is one example. Regulatory agencies such as the Food and Drug Administration are increasing standards by which drugs are evaluated for cardiac toxicity related to QT interval prolongation. It is imperative that clinicians be knowledgeable of the risk factors for QT prolongation and avoid the use of culpable agents in patients at risk for QT prolongation.     

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.     

Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview.

The long and growing list of non-antiarrhythmic drugs associated with prolongation of the QT interval of the electrocardiogram has generated concern not only for regulatory interventions leading to drug withdrawal, but also for the unjustified view that QT prolongation is usually an intrinsic effect of a whole therapeutic class [e.g. histamine H(1) receptor antagonists (antihistamines)], whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. We provide an overview of the different classes of non-antiarrhythmic drugs reported to prolong the QT interval (e.g. antihistamines, antipsychotics, antidepressants and macrolides) and discusses the clinical relevance of the QT prolonging effect. Drug-induced torsade de pointes are sometimes considered idiosyncratic, totally unpredictable adverse drug reactions, whereas a number of risk factors for their occurrence is now recognised. Widespread knowledge of these risk factors and implementation of a comprehensive list of QT prolonging drugs becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia, hypocalcaemia), impaired hepatic/renal function, concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class I or III antiarrhythmic agents). This review provides insight into the strategies that should be followed during a drug development program when a drug is suspected to affect the QT interval. The factors limiting the predictive value of preclinical and clinical studies are also outlined. The sensitivity of preclinical tests (i.e. their ability to label as positive those drugs with a real risk of inducing QT pronglation in humans) is sufficiently good, but their specificity (i.e. their ability to label as negative those drugs carrying no risk) is not well established. Verapamil is a notable example of a false positive: it blocks human ether-a-go-go-related (HERG) K(+) channels, but is reported to have little potential to trigger torsade de pointes. Although inhibition of HERG K(+) channels has been proposed as a primary test for screening purposes, it is important to remember that several ion currents are involved in the generation of the cardiac potential and that metabolites must be specifically tested in this in vitro test. At the present state of knowledge, no preclinical model has an absolute predictive value or can be considered as a gold standard. Therefore, the use of several models facilitates decision making and is recommended by most experts in the field.     

Antipsychotic-induced sudden cardiac death: examination of an atypical reaction

Following the publication of a recent study, which linked antipsychotics to sudden cardiac death, the safety of both typical and atypical antipsychotics has once again been questioned. Sudden cardiac death resulting from ventricular arrhythmias remains a significant public health concern, with over 300,000 deaths per year in the US alone. Long QT syndrome (LQTS) is an important cause of sudden cardiac death in which both congenital and acquired lesions in cardiac ionic channels impair myocardial repolarization and predispose the heart to developing lethal ventricular rhythms, including torsade de pointes, which may degenerate into ventricular fibrillation. Congenital LQTS is a relatively rare condition; however, acquired LQTS and arrhythmogenesis occurring through the unwanted pharmacological effects of a wide range of medications has become one of the largest problems facing the pharmaceutical industry today. This article examines recent findings linking antipsychotics to ventricular arrhythmias and explores potential new strategies to reduce the incidence of drug-induced sudden cardiac death.     

药物致Q-T间期延长的文献分析

近年来,临床实践有许多药物都会导致Q-T间期延长甚至尖端扭转型室性心律失常（TdP）。本文通过对1979年-2013年国内医药期刊公开报道的药物致Q-T间期延长的个案进行统计和分析,总结了56个病例的一般情况、引起Q-T间期延长的药物、发生时间及转归等,致Q-T间期延长药物中排在前三位的分别为抗心律失常药、抗微生物药、抗组胺药。大部分患者在用药后一个月内出现,停药及对症治疗后好转。临床医师应正确地认识药物致Q-T间期延长发生机制和易感因素,才能保证临床安全有效地使用药物。     

Statistical analysis methods for QT/QTc prolongation

Prolonged QT interval is associated with life-threatening arrhythmias. Regulatory authorities have paid special attention to investigating the drug-induced delay of cardiac repolarization. Studies aimed at evaluating QT prolongation have become a routine part of safety packages across the pharmaceutical industry. However, the assessment of QT interval prolongation on the surface electrocardiogram is complicated by the fact that many factors influence the duration of the QT interval, among which heart rate plays a predominant role. Some widely used corrections of the QT interval for varying heart rate are known to be inadequate. Many alternatives have been proposed in the literature. Using information obtained from Eli Lilly thorough QT studies, we examine the performance of several approaches to the analysis of QT changes, including subject-specific (individual) QT corrections and model-based QT analysis methods. The simulation results indicate that the mixed-effects modeling approach proposed in this paper is more powerful than the other methods, all of which are commonly used in QT studies.     

Statistical Analysis Methods For QT/QTc Prolongation

Prolonged QT interval is associated with life-threatening arrhythmias. Regulatory authorities have paid special attention to investigating the drug-induced delay of cardiac repolarization. Studies aimed at evaluating QT prolongation have become a routine part of safety packages across the pharmaceutical industry. However, the assessment of QT interval prolongation on the surface electrocardiogram is complicated by the fact that many factors influence the duration of the QT interval, among which heart rate plays a predominant role. Some widely used corrections of the QT interval for varying heart rate are known to be inadequate. Many alternatives have been proposed in the literature. Using information obtained from Eli Lilly thorough QT studies, we examine the performance of several approaches to the analysis of QT changes, including subject-specific (individual) QT corrections and model-based QT analysis methods. The simulation results indicate that the mixed-effects modeling approach proposed in this paper is more powerful than the other methods, all of which are commonly used in QT studies.     

抗新型冠状病毒药物致QT间期延长的文献复习及药学监护

本文对新型冠状病毒肺炎患者临床用药方案涉及的抗病毒药物致QT间期延长的文献报道情况进行复习。根据目前文献复习结果可知,洛匹那韦/利托那韦和磷酸氯喹存在引起QT间期延长进而引发尖端扭转型室速的潜在风险。在新型冠状病毒肺炎患者中使用此类药物需关注由此带来的用药风险,熟悉临床上常用的可引起QT间期延长的药物,提高识别患者QT间期延长的易感因素和药物相互作用的能力,重视心电图、电解质管理来预防临床潜在的药物致急性心律失常事件,以降低新型冠状病毒肺炎患者的药物不良反应,避免药源性损害。     

Cardiac ion channel safety profiling on the IonWorks Quattro automated patch clamp system

The normal electrophysiologic behavior of the heart is determined by the integrated activity of specific cardiac ionic currents. Mutations in genes encoding the molecular components of individual cardiac ion currents have been shown to result in multiple cardiac arrhythmia syndromes. Presently, 12 genes associated with inherited long QT syndrome (LQTS) have been identified, and the most common mutations are in the hKCNQ1 (LQT1, Jervell and Lange-Nielson syndrome), hKCNH2 (LQT2), and hSCN5A (LQT3, Brugada syndrome) genes. Several drugs have been withdrawn from the market or received black box labeling due to clinical cases of QT interval prolongation, ventricular arrhythmias, and sudden death. Other drugs have been denied regulatory approval owing to their potential for QT interval prolongation. Further, off-target activity of drugs on cardiac ion channels has been shown to be associated with increased mortality in patients with underlying cardiovascular diseases. Since clinical arrhythmia risk is a major cause for compound termination, preclinical profiling for off-target cardiac ion channel interactions early in the drug discovery process has become common practice in the pharmaceutical industry. In the present study, we report assay development for three cardiac ion channels (hKCNQ1/minK, hCa(v)1.2, and hNa(v)1.5) on the IonWorks Quattro? system. We demonstrate that these assays can be used as reliable pharmacological profiling tools for cardiac ion channel inhibition to assess compounds for cardiac liability during drug discovery.     

The impact of drug-induced QT interval prolongation on drug discovery and development

During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval, and an increased propensity to develop a ventricular tachyarrhythmia called Torsades de Pointes. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory review and is considered a significant risk factor for predicting human safety of New Chemical Entities. Consequently, pharmaceutical companies are striving to improve the drug discovery and development process to identify, as early as possible, the risk of novel agents, or their metabolites, of causing QT interval prolongation and to make appropriate go/no-go decisions or modify their development programme accordingly.     

Screening lead compounds for QT interval prolongation

The late detection of cardiotoxic side effects, such as QT prolongation, induced by compounds of pharmacological interest can dramatically impede drug discovery and development projects, and consequently increase their cost. The launch of new drugs with undetected cardiotoxic side effects could have hazardous consequences and could trigger lethal cardiac dysrhythmias in patients. It is desirable, therefore, to test for the potential cardiotoxic side effects of compounds at an early stage of drug development. Electrophysiological test systems and cellular-based fluorometric high-throughput assays are now available for cloned human cardiac ion channels. These test systems are important tools in the preclinical safety evaluation of drugs and newly developed compounds.     

hERG potassium channels and the structural basis of drug-induced arrhythmias

hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K (+) channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias.     

Pharmacogenomics and acquired long QT syndrome

During the past decade pharmaceutical companies have been faced with the withdrawal of some of their marketed drugs because of rare, yet lethal, postmarketing reports associated with ventricular arrhythmias. The implicated drugs include antiarrhythmics, but also non-cardiac drugs, such as histamine blockers, antipsychotics, and antibiotics. These undesired effects involve prolongation of the QT interval, which may lead to characteristic ventricular tachyarrhythmias, known as torsades de pointes. These clinical symptoms of the acquired long QT syndrome (LQTS) are also found in an inherited form of the disease, called congenital LQTS. Nowadays, a number of environmental (non-genetic) and genetic risk factors for acquired LQTS have been described. Non-genetic factors include female gender, hypokalemia, and other heart diseases. The knowledge of genetic risk factors is emerging rapidly. During the last decade, mutations in several genes encoding ion channels have been shown to cause congenital LQTS. In acquired LQTS, a number of 'silent' mutation carriers in these LQTS genes have been identified, and functional polymorphisms in the same genes have been found that are associated with an increased vulnerability for the disease. Furthermore, there is also evidence that interindividual differences in drug metabolism, caused by functional polymorphisms in drug-metabolizing enzyme genes, may be a risk factor for acquired LQTS, especially if multiple drugs are involved. This review evaluates the current knowledge on these risk factors for acquired LQTS, with an emphasis on the genetic risk factors. It also assesses the potential to develop pharmacogenetic tests that will enable clinicians and pharmaceutical companies to identify at an early stage patients or individuals in the general population who are at risk of acquired LQTS.