Risk Of QT Interval Prolongation Research Articles

Comparison of electrocardiographic analysis for risk of QT interval prolongation using safety pharmacology and toxicological studies

Testing for possible cardiovascular side effects of new drugs has been an essential part of drug development for years. A more detailed analysis of the electrocardiogram (ECG) to detect effects on ventricular repolarization (effects on the QT interval), as a marker for possible proarrhythmic potential has been added to that evaluation in recent years. State-of-the art evaluation of drug-induced effects on the QT interval have evolved, but due to the complexity of the assessment, the trend in safety pharmacology studies has been to collect large numbers of high quality ECGs to allow for a robust assessment including the influence of heart rate on the QT interval apart from possible drug-induced effects. Since an assessment of the ECG is often included in toxicological studies, one can consider making such an assessment using ECG data from routine toxicological studies. This review summarizes various aspects of both safety pharmacology and toxicology studies with regards to their impact on the quality and quantity of ECG data that one can reasonably derive. We conclude that ECG data from toxicological studies can offer complementary ECG data that can strengthen a risk assessment. However, for the great majority of standard toxicity studies conducted, the ECG data collected do not permit an adequate assessment of drug-induced effects on the QT interval with the sensitivity expected from the ICH S7B guidelines. Furthermore, sponsors should be discouraged from performing any analyses on low quality ECGs to avoid generating misleading data. Substantial improvements in ECG quality and quantity are available, thereby making a QT interval assessment within the context of a standard toxicological study feasible, but these methods may require a larger commitment of resources from the sponsor. From the viewpoint of risk mitigation and limiting the attrition of promising new therapies, a commitment of resources to insure ECG data quality in either toxicology or safety pharmacology studies may be well justified.

Strategies to reduce the risk of drug‐induced QT interval prolongation: a pharmaceutical company perspective

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

Clinical Trials in the Wake of Vioxx

Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion. Editorial p 2173 These termination decisions are invariably complex and involve important subjective and ethical elements.1 Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy. The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.2 Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.3 The possibility of cardiac toxicity in human trials was recognized in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.4 Meta-analyses, database studies, and prospective trials further corroborated cardiac toxicity,5–8 and Merck voluntarily withdrew rofecoxib from the US market on September 30, 2004,9 amid widespread criticism of both Merck and the Food and Drug Administration.10,11 In the wake …

Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks™ HT

Introduction Regulatory and competitive pressure to reduce the QT interval prolongation risk of potential new drugs has led to focus on methods to test for inhibition of the human ether-a-go-go-related gene (hERG)-encoded K + channel, the primary molecular target underlying this safety issue. Here we describe the validation of a method that combines medium-throughput with direct assessment of channel function. Methods The electrophysiological and pharmacological properties of hERG were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks™ HT). A pharmacological comparison was also made between IonWorks™ HT and an indirect assay (Rb + efflux). Results Basic electrophysiological properties of hERG were similar whether recorded conventionally (HEK cells) or using IonWorks™ HT (CHO cells): for example, tail current V ½ − 12.1 ± 5.0 mV (32) for conventional and − 9.5 ± 6.0 mV (46) for IonWorks™ HT (mean ± S.D. ( n)). A key finding was that as the number of cells per well was increased in IonWorks™ HT, the potency reported for a given compound decreased. Using the lowest possible cell concentration (250,000 cells/ml) and 89 compounds spanning a broad potency range, the pIC 50 values from IonWorks™ HT (CHO-hERG) were found to correlate well with those obtained using conventional methodology (HEK-hERG)( r = 0.90; p < 0.001). Further validation using CHO-hERG cells with both methods confirmed the correlation ( r = 0.94; p < 0.001). In contrast, a comparison of IonWorks™ HT and Rb + efflux data with 649 compounds using CHO-hERG cells showed that the indirect assay consistently reported compounds as being, on average, 6-fold less potent, though the differences varied depending on chemical series. Discussion The main finding of this work is that providing a relatively low cell concentration is used in IonWorks™ HT, the potency information generated correlates well with that determined using conventional electrophysiology. The effect on potency of increasing cell concentration may relate to a reduced free concentration of test compound owing to partitioning into cell membranes. In summary, the IonWorks™ HT hERG assay can generate pIC 50 values based on a direct assessment of channel function in a timeframe short enough to influence chemical design.

Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients

Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence. To evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval. This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates. Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals. Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4.

QT Interval Prolongation: And the Beat Goes on

Consideration of QT interval prolongation and the risk for developing torsade de pointes is a critical issue in the evaluation of new bioactive agents. Over the past several years, there has been a dramatic increase in understanding the I(Kr) channel and its role in the duration of the action potential and cardiac repolarization. Furthermore, a variety of factors and situations have been identified that can increase the risk of QT interval prolongation. In this brief summary, an overview of the hERG channel and QT prolongation will be presented. The basic electro-physiology of the heart, the related action potentials, and pre-clinical assays is reviewed. Further, an introduction to the current status of in silico efforts in predicting potential hERG blockers is discussed. Lastly, the strengths and weaknesses of each modeling method is presented along with insight to the appropriate use of each model.

Nonclinical proarrhythmia models: Predicting Torsades de Pointes

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I Kr (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

A survey of health care practitioners' knowledge of the QT interval.

To assess health care practitioners' ability to correctly measure the QT interval, and to identify factors and medications that may increase the risk of QT-interval prolongation and torsades de pointes. A cross-sectional analysis of a survey administered between April 2002 and March 2003. Health care practitioners attending Grand Rounds Conferences at 6 academic institutions in the United States in internal medicine and psychiatry and at 6 community hospitals in the same geographical areas as the academic institutions. Anonymous, self-administered questionnaire that included 20 questions on the QT interval. Of approximately 826 attendees, 517 (63%) completed the survey. Of about 608 attendees of internal medicine conferences, 371 (61%) responded, and of about 208 attendees of psychiatry conferences, 146 (67%) responded. Of a total number of 20 questions, the median number of correct answers for the whole group was 10 (interquartile range 7-13). The median number of correct answers for internists was 12 (interquartile range 9-13), for psychiatrists 10 (interquartile range 7-13), and for other specialists 10 (interquartile range 5-13). Respondents who graduated between 1990 and 1999 and academicians performed significantly better overall than other respondents. Of the 517 respondents, 224 (43%) measured the QT interval correctly. Physicians in training and academicians were more likely to measure the QT interval correctly. The majority of health care practitioners cannot correctly measure the QT interval and cannot correctly identify factors and medications that can prolong the QT interval. Our findings suggest that greater attention to the QT interval is warranted to ensure safer use of QT prolonging medications.

QT PRODACT: Sensitivity and Specificity of the Canine Telemetry Assay for Detecting Drug-Induced QT Interval Prolongation

The purpose of this investigation was to define the sensitivity and specificity of the canine telemetry assay for detecting drug-induced QT interval prolongation. Data from twelve studies generated in the QT PRODACT project were used in this investigation. The study design was a 4 × 4 Latin square cross-over design and included the following drugs: MK-499, E-4031, terfenadine, haloperidol, cisapride, bepridil, propranolol, diphenhydramine, captopril, verapamil, amoxicillin, and ciprofloxacin. The estimated root squared error of the model, which estimated the slope of the QT-RR relationships for each animal, for all dogs during the pre-dosing period was 5.45%. Using the QT-RR model, the sensitivity and specificity in each cutoff value that judges QT prolongation were estimated based on the experiment errors and measurement errors in the 12 studies. When the cutoff value was 5%, the sensitivity in 10% prolongation was 0.978 and the specificity in 0% was 0.996. In conclusion, it was judged that a 5% cutoff value for changes in heart rate corrected QT interval using the canine telemetry assay is practical, and the sensitivity and specificity of the telemetry assay are very high when using the analytical method presented here. Based upon this information, the canine telemetry assay using the individual subject heart rate correction model is recommended as a sensitive test system for the in vivo assessment of risk for QT interval prolongation.

QT PRODACT: A Multi-site Study of In Vitro Action Potential Assays on 21 Compounds in Isolated Guinea-Pig Papillary Muscles

To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (IKr) prolonged action potential duration at 90% repolarization (APD90) in a concentration-dependent manner, those showing Ca2+ current (ICa) inhibition shortened APD30, and those showing Na+ current (INa) inhibition decreased action potential amplitude (APA) and Vmax. Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD90, probably due to their blockade of INa and/or ICa, sometimes leading to a false-negative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with IKr-blocking activity prolonged APD30–90 regardless of their INa- and/or ICa-blocking activities, suggesting that APD30–90 is a useful parameter for evaluating the IKr-blocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD90 and APD30–90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies.Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A1

QT PRODACT: Database Construction for the Evaluation of the Risk of QT Interval Prolongation by Drugs in Japan

QT PRODACT: Database Construction for the Evaluation of the Risk of QT Interval Prolongation by Drugs in Japan

Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy.

More than 70 drugs present on the Swiss market can cause drug-induced long QT syndrome (LQTS), which is associated with torsades de pointes (TdP) arrhythmias, potentially leading to sudden cardiac death. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ERG (hERG) channel involved in the repolarisation phase of the cardiac action potential, and thus lengthen the QT interval. Beside the well-known QT interval prolonging action of class IA, IC and III anti-arrhythmic drugs, many antibiotics, neurotropic, antifungal, and antimalarial drugs are also able to cause drug-induced LQTS. Reviewing the literature indicates that the risk of QT interval prolongation and TdP is increased in females, in patients with organic heart diseases and hypokalaemia. Furthermore in a few cases, genetic factors have also been reported. However thus far, no genetic test is available to detect at-risk patients, and in consequence, drug prescribers are still relying only on the clinical history and findings to perform an evaluation of the risk. Treatment of drug-induced LQTS and TdP includes identifying and withdrawing the culprit drug(s), infusing magnesium and, in resistant cases acceleration of the heart rate. In this review article we provide a list of QT interval prolonging drugs adapted to the pharmaceuticals found on the Swiss market that can be used as a check-list for drug prescribers and at-risk patients.

Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy.

More than 70 drugs present on the Swiss market can cause drug-induced long QT syndrome (LQTS), which is associated with torsades de pointes (TdP) arrhythmias, potentially leading to sudden cardiac death. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ERG (hERG) channel involved in the repolarisation phase of the cardiac action potential, and thus lengthen the QT interval. Beside the well-known QT interval prolonging action of class IA, IC and III anti-arrhythmic drugs, many antibiotics, neurotropic, antifungal, and antimalarial drugs are also able to cause drug-induced LQTS. Reviewing the literature indicates that the risk of QT interval prolongation and TdP is increased in females, in patients with organic heart diseases and hypokalaemia. Furthermore in a few cases, genetic factors have also been reported. However thus far, no genetic test is available to detect at-risk patients, and in consequence, drug prescribers are still relying only on the clinical history and findings to perform an evaluation of the risk. Treatment of drug-induced LQTS and TdP includes identifying and withdrawing the culprit drug(s), infusing magnesium and, in resistant cases acceleration of the heart rate. In this review article we provide a list of QT interval prolonging drugs adapted to the pharmaceuticals found on the Swiss market that can be used as a check-list for drug prescribers and at-risk patients.

Lidoflazine is a high affinity blocker of the HERG K +channel

Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K + channel α subunit (encoded by HERG – human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I HERG) recorded from HEK 293 cells stably expressing wild-type HERG (IC 50 of ~16 nM). It was ~13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I HERG inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug’s action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the α subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.

Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene—without QT interval prolongation

The acquired form of the long-QT syndrome (LQTS) is a major safety consideration for the development and subsequent use of both cardiac and non-cardiac drugs; it is usually associated with pharmacological inhibition of cardiac HERG-encoded potassium channels. Clomiphene is an anti-estrogen agent used extensively in the treatment of infertility and is not associated with a risk of QT interval prolongation, in contrast to a structurally related compound tamoxifen. We describe here a potent inhibitory effect (IC 50=0.18 μM) of clomiphene on HERG ionic current ( I HERG) recorded from a mammalian cell line expressing HERG channels. Inhibition of I HERG by clomiphene showed voltage-dependence and developed quickly following membrane depolarisation, indicating contingency of block on HERG channel gating. At 100 nM, clomiphene and the related anti-estrogen tamoxifen produced similar levels of I HERG blockade ( p>0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on I HERG, clomiphene produced no significant effect at 1 μM on uncorrected QT interval ( p>0.1) nor on rate-corrected QT interval (QT c; p>0.1 for QT c determined using Van de Water’s formula). The disparity between clomiphene’s potent I HERG inhibition and its lack of effect on the QT interval underscores the notion that I HERG pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs.

5-HT2A antagonism does not affect catalepsy in rats

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on IKr (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP.In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others.Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

Effect of cisapride on QT interval in patients with end-stage renal disease

C isapride (Propulsid, Janssen Pharmaceutica, Titusville, New Jersey) is an orally administered prokinetic agent used in the treatment of dyspepsia, diabetic gastroparesis, and gastroesophageal reflux disease. Cisapride increases gastrointestinal tract motility by enhancing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus.1 Although the drug is useful and generally well tolerated, numerous cases of QT interval prolongation, torsades de pointes, and sudden death have been reported.2–4 Cisapride-induced rhythm disturbances are most likely caused by blockade of the rapid component of the potassium rectifier current via high-affinity blockade of the human cardiac potassium channel HERG.5–7 This leads to delayed repolarization, early afterdepolarization, and potentially torsades de pointes. Clinically, cisapride-induced rhythm disturbances can be explained by pharmacokinetic and/or pharmacodynamic mechanisms. Pharmacokinetic mechanisms have been attributed to situations that result in an increase in cisapride blood concentrations secondary to inhibition of cytochrome p450 3A4 (CYP3A4) metabolism (the CYP isoenzyme primarily responsible for cisapride metabolism) by concomitant drugs3,8 (e.g., clarithromycin), disease-related alterations in drug removal (e.g., hepatic dysfunction), or higher than recommended cisapride doses.9 In fact, it has been suggested that the degree of QT interval prolongation is directly related to the cisapride serum concentration.8 Pharmacodynamic mechanisms include factors leading to additional blockade of cardiac potassium currents (concomitant drugs, diseases, electrolyte disturbances, and so forth)4,10 In May 1998, Janssen Pharmaceutica introduced labeling changes for cisapride. New contraindications to the drug were added, which included patients with renal failure. Cisapride’s manufacturer has reported that patients with renal failure were “predisposed to arrhythmias with cisapride.”11 More recently, Janssen Pharmaceutica announced that it had voluntarily stopped marketing cisapride in the United States effective July14, 2000.12 Patients who have no success with other therapies and who meet carefully defined eligibility criteria will be eligible to receive cisapride in the manufacturer’s “investigational limited-access program.”13 Two published case reports describe the occurrence of torsades de pointes in patients with end-stage renal disease (ESRD) receiving cisapride and clarithromycin2 (a well-known inhibitor of CYP3A4). It is apparent that patients with ESRD receiving drugs known to inhibit cisapride metabolism are at risk for the development of QT interval prolongation and subsequent cardiac arrhythmias. No publication to date has documented the proarrhythmic action of cisapride in patients with ESRD, in the absence of interacting drugs. The purpose of this study was to examine the degree of cisapride-induced corrected QT interval (QTc) prolongation and QT dispersion in patients with ESRD in a typical clinical setting. • • • Nine subjects with ESRD receiving dialysis treatment at the Indiana University Medical Center Outpatient Dialysis Unit were included in this study. Subjects were included in the study if their physician wanted to discontinue cisapride therapy, and they were aged .18 years of age, were receiving thrice weekly maintenance on hemodialysis, and were currently taking oral cisapride chronically. Subjects were excluded if they had serum electrolyte disturbances that may have induced QT interval changes (e.g., persistent hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia before hemodialysis sessions), or were taking medications, which, when used alone or in combination with cisapride, increase the risk of QT interval prolongation. The protocol was approved by the Indiana University-Purdue University-Indianapolis Institutional Review Board and each subject gave written informed consent before enrollment in the study. Subjects’ medical charts were reviewed and data collected for age, sex, concomitant diseases, details of cisapride therapy (indication, dose, duration of therapy), concomitant drug therapy, and serum electrolyte concentrations. Cardiac rhythm, ventricular rate, and QT intervals were determined from 12-lead electrocardiograms recorded at 50 mm/s immediately before the regularly scheduled hemodialysis session. Electrocardiograms were obtained during cisapride therapy and after cisapride had been discontinued for at least 2 weeks. The terminal elimination half-life of cisapride in a published study of patients with ESRD was 9.6 6 3.3 hours (range 5.1 to 14.1).14 Consequently, the 2-week time period allowed nearly complete elimination of cisapride from the systemic circulation. All electrocardiograms were evaluated by 2 cardiologists blinded to the treatment phase. Heart rate was determined as the average of the RR intervals obtained From the Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, Indianapolis; and the Divisions of Nephrology and Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana. Dr. Sowinski’s address is: Purdue University, Department of Pharmacy Practice, D711 Myers Building, WHS, 1001 W. 10th Street, Indianapolis, Indiana 46202–2879. E-mail: ksowinsk@iupui.edu. Manuscript received January 24, 2000; revised manuscript received and accepted May 1, 2000.

Investigation of the mechanism by which ketanserin increases cardiac action potential duration

In the current ICH S7B guideline, in vitro evaluation of proarrhythmic liability is limited to the risk of QT interval prolongation, whilst the effect of new chemical entities on cardiac conductivity is often overlooked. The aim of this work was to compare the effects of the sodium channel blocker, lidocaine in three in vitro safety pharmacology models: hNav1.5 channel test, atrial action potential (AP) and Purkinje fiber AP and to identify the most sensitive model for detecting cardiac conduction slowing.Whole-cell patch‐clamp methods were used to record the sodium current (INa) encoded by hNav1.5 in stably transfected HEK293 cells at ambient temperature. Transmembrane APs were recorded in rabbit Purkinje fibers and rabbit and guinea-pig left stimulated atria at physiological temperature. Parameters involved in depolarization or repolarization were reported.Lidocaine (from 10 to 1000 μM) decreased the amplitude of INa (IC50: 256 ± 37 μM) in a concentration-dependent manner. In the Purkinje fiber assay, lidocaine (10, 30 and 100 μM) had no effects on maximal upstroke velocity (Vmax), but shortened AP duration at 90% repolarization (APD90). At 30 and 100 μM, lidocaine also increased AP triangulation. In guinea-pig atria, lidocaine decreased Vmax starting from 30 μM and conduction velocity (CV) at 100 μM, but had no effects on other parameters. In rabbit atria, lidocaine decreased Vmax and CV at 100 μM without affecting APD90. The effects of 100 μM lidocaine on Vmax and CV were more marked in rabbit than in guinea-pig atria.Rabbit atria are more sensitive than rabbit Purkinje fibers or guinea-pig atria for detecting lidocaine-induced cardiac conduction slowing. These data suggest that isolated rabbit atria in addition to the hNav1.5 channel assay could be relevant models to predict drug-induced conduction slowing.