Anthony A. Fossa

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During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval, and an increased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.

Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects

This White Paper, written collaboratively by members of the Cardiac Safety Research Consortium from academia, industry, and regulatory agencies, discusses different methods to characterize the QT effects for drugs that have a substantial direct or indirect effect on heart rate. Descriptions and applications are provided for individualized QT-R-R correction, Holter bin, dynamic QT beat-to-beat, pharmacokinetic-pharmacodynamic modeling, and QT assessment at constant heart rate. Most of these techniques are optimally performed using continuous electrocardiogram data obtained in clinical studies designed to characterize a drugs effect on the QT interval. An important study design element is the collection of drug-free data over a range of heart rates seen on treatment. The range of heart rates is increased at baseline by using ambulatory electrocardiogram recordings in addition to those collected under semisupine, resting conditions. Discussions in this study summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further increase our knowledge and understanding of this topic.

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

Oral administration of the angiotensin II receptor subtype 1 (AT1) antagonist DuP 753 causes long-lasting lowering of mean arterial pressure in spontaneously hypertensive rats. We examined whether the antihypertensive action of DuP 753 is a result of inhibition of brain angiotensin II. In normal spontaneously hypertensive rats, we found that intracerebroventricular DuP 753 (10 μg) blocked the pressor action of intracerebroventricular angiotensin II (100 ng); however, intracerebroventricular DuP 753 (10 μg) had no effect on the pressor response to 300 ng/kg angiotensin II administered intravenously (48±3 mm Hg in the presence of intracerebroventricular DuP 753 versus 49±4 mm Hg in its absence). In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 μg caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours. In contrast to its central effects, we found that oral DuP 753 (10 or 30 mg/kg) in normal spontaneously hypertensive rats resulted in sustained mean arterial pressure decreases of up to −74 mm Hg. These data suggest that, although the pressor effect of brain angiotensin II is mediated by the AT1 receptor, blockade of these receptors does not lower blood pressure in spontaneously hypertensive rats. In the spontaneously hypertensive rat, DuP 753 depresses blood pressure by blockade of peripheral, not central, AT1 receptors.

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC20 concentrations of 31 μM (moxifloxacin), 21 μM (erythromycin), and 11 μM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 μM). Erythromycin also increased MAPD at its highest free drug concentration (58 μM), but alternans occurred at a relatively lower therapeutic multiple (13.9 μM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 μM). The relative risk at therapeutic concentrations is erythromycin > moxifloxacin > telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

Analyses of Dynamic Beat-to-Beat QT-TQ Interval (ECG Restitution) Changes in Humans under Normal Sinus Rhythm and Prior to an Event of Torsades de Pointes during QT Prolongation Caused by Sotalol

Background: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat‐to‐beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm.

Chronic Monitoring of Cardiovascular Function in the Conscious Guinea Pig Using Radio-Telemetry

An implantable radio-telemetry device for chronic monitoring of arterial pressure and heart rate in the conscious guinea pig was validated against measurements using an exteriorized, indwelling catheter. There were no significant differences between simultaneous measurements in animals instrumented with both the telemetry system and the conventional catheter (implanted 24 hrs prior to comparisons) in response to a variety of vasoactive agents. The device was shown to be accurate up to 3 weeks after implantation (longest time point tested). Resting pressures and heart rates in the telemetered guinea pig were stable in 100% of the animals tested. In contrast, animals instrumented with only exteriorized catheters showed a significant decline in pressure by 8 days after surgery and a 39% attrition rate due to loss of catheter patency. Performance of the telemetric device was examined in both normal and sodium-deficient animals, since the latter is a useful normotensive model in which blood pressure is rendered highly renin-dependent for evaluating the efficacy of potential antihypertensive agents that target the renin-angiotensin system. The telemetered guinea pig is an appropriate model for assessing responses to chronic exposure of cardiovascular agents.

Baseline Values and Sotalol‐Induced Changes of Ventricular Repolarization Duration, Heterogeneity, and Instability in Patients With a History of Drug‐Induced Torsades de Pointes

The authors investigated whether computerized parameters quantifying ventricular repolarization delay, heterogeneity, and instability characterize individuals who developed drug‐induced Torsades de Pointes. Assessing an individuals propensity to Torsades de Pointes when exposed to a QT‐prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five‐minute digital 12‐lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of Torsades de Pointes in the context of a QT‐prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of Torsades de Pointes, the baseline electrocardiograms of patients with a history of Torsades de Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 ± 13 vs 35 ± 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with Torsades de Pointes revealed a delay of the terminal part of the T wave that was not present in patients without Torsades de Pointes (TpTe: 27 ± 40 vs −1 ± 21 ms, P = .02; LRD70%: 20 ± 29 vs 2 ± 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of Torsades de Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol‐induced prolongation of the terminal part of the T wave.

Assessing QT prolongation in conscious dogs: Validation of a beat-to-beat method

A model of sling-trained, conscious mongrel dogs instrumented with telemetric arterial pressure transmitters and ECG leads was validated for assessment of the QT-RR interval relationship at clinically used free and total plasma concentrations of positive and negative standards with known outcomes. The beat-to-beat technique for assessing the dynamic boundaries of the individual cardiac cycles was compared to the same data with typically used averaging techniques and corrections applied. Positive standards E-4031, cisapride, terodiline, and terfenadine showed increased sensitivity toward detection at clinically relevant levels when an outlier analysis of beats beyond the normal autonomic boundary is applied. Since methods to correct the QT interval for heart rate are often confounded with changes in autonomic state, a validation of the changes with reflex tachycardia induced by vasodilatation after nitroprusside and reflex bradycardia induced by sudden vasoconstriction with phenylephrine where shown to be differentiated from direct effects of repolarization with E-4031. These changes were also demonstrated to be identical to effects observed in humans after standing or challenged with a similar dose of phenylephrine. The conscious dog is also a sensitive model for studying the arrhythmia liability induced by beat-to-beat changes in cardiac ECG restitution (the relationship between QT and TQ intervals) and hysteresis. However, some caveats based on observations may need to be considered due to inherent differences in QT intervals and sinus arrhythmia between canines and humans.

The use of beat-to-beat electrocardiogram analysis to distinguish QT/QTc interval changes caused by moxifloxacin from those caused by vardenafil.

QT correction factors (QTc) can cause errors in the interpretation of drug effects on cardiac repolarization because they do not adequately differentiate changes when heart rate or autonomic state deviates from the baseline QT/RR interval relationship. The purpose of our study was to determine whether the new method of QT interval dynamic beat–to–beat (QTbtb) analysis could better discriminate between impaired repolarization caused by moxifloxacin and normal autonomic changes induced by subtle reflex tachycardia after vardenafil. Moxifloxacin produced maximum mean increases of 13–14 ms in QTbtb, QTcF, and QTcI after 4 h. After vardenafil administration, a 10–ms effect could be excluded at all time points with QTbtb but not with QTcF or QTcI. Subset analysis of the vardenafil upper pharmacokinetic quartile showed that the upper bound of QTcF and QTcI was >10 ms, whereas that of QTbtb was <8 ms. This study demonstrated that newer methods of electrocardiogram (ECG) analysis can differentiate changes in the QT interval to improve identification of proarrhythmia risk.

Pre-Clinical Assessment of Drug-Induced QT Interval Prolongation. Current Issues and Impact on Drug Discovery

Publisher Summary This chapter addresses the issue of drug-induced QT prolongation and examines its impact on drug-development programs in the pharmaceutical industry. Prolongation of the QT interval in patients is usually observed in response to an underlying medical condition, or in association with drug treatment, or else in patients afflicted with one of the congenital long-QT syndromes. Genetic studies have identified at least six genes that, if mutated, result in ion channel malfunction that can cause the long-QT syndrome. In the large majority of cases, drugs that prolong the QT interval and cause TdP inhibit human Ether-a-go-go-Related Gene (HERG) or I Kr at therapeutic, or supra therapeutic concentrations. Clinicians and regulators use the QT interval as a surrogate marker for the prediction of adverse effects such as TdP. Rightfully or not, it is currently assumed that even small changes in the QT interval indicate some risk of TdP, and there is presently no well established threshold below which a prolonged QT interval is believed to be harmless. Many different factors that influence cardiac repolarization and the duration of the QT interval have been associated with an increased risk of drug-induced arrhythmias. These include age (very young and elderly), gender (female > male), heart rate (bradycardia), cardiac disorders, electrolyte imbalance, disease states (hepatic and renal), and concomitant medication.