Absence Of QT Prolongation Research Articles

Abstract #1403093: Absence of QT Prolongation Associated with Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Cushing Syndrome

QT prolongation is a significant concern for patients with Cushing syndrome (CS). Approximately 26% of men with CS present with QT prolongation, and the risk of cardiac arrhythmic events correlates with the extent of QT prolongation. All currently approved CS medications are associated with QT prolongation, posing a significant risk for the management of CS. Here, we evaluate the impact relacorilant, an investigational selective glucocorticoid receptor modulator, on QT prolongation in healthy volunteers and patients with CS. In a 3-part, single-center, first-in-human study (NCT03508635, “phase 1 study”), 103 healthy volunteers received single or multiple ascending doses of relacorilant (up to 500 mg QD) for up to 14 days; 24 received placebo. In a randomized, partial double-blind, crossover thorough QT study (NCT04795479, “TQT study”), the effect of multiple therapeutic (400 mg QD, n=25) and supra-therapeutic (800 mg QD, n=28) doses of relacorilant on cardiac repolarization was studied in healthy volunteers. A single dose of moxifloxacin (400 mg, n=28) was used as a positive control; 29 participants received placebo. In a single-arm, open-label phase 2 study (NCT02804750, “CS study”), 17 patients with CS received low-dose relacorilant (100–200 mg QD) for 12 weeks and 18 patients received high-dose relacorilant (250–400 mg QD) for 16 weeks. In all studies, ECG data were collected, and the heart rate-corrected QT interval using Fridericia’s formula (QTcF) was assessed. In the phase 1 study, relacorilant up to 500 mg daily did not adversely affect ECG parameters. An effect on placebo-corrected change from baseline QTcF (ΔΔQTcF) above 10 msec was excluded. In the TQT study, moxifloxacin control showed the expected QT prolongation, confirming assay sensitivity. Relacorilant had no adverse effects on ECG parameters and showed effects similar to placebo. Based on concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 msec was excluded within the full observed range of relacorilant plasma concentrations. These results constitute a negative TQT study. The CS study confirmed that these favorable findings also apply to patients with CS: Throughout the CS study, no significant changes in median QTcF were observed in either dose group. There is an unmet need for medications to treat CS that do not cause QT prolongation and possibly fatal arrhythmias. Based on the TQT study and supported by additional data in healthy volunteers and patients with CS, relacorilant did not show an association with QT prolongation.

Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large-variability, and high-risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30-fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10-fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10-fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.

A TRIGGER FOR AN ARRHYTHMIC STORM: SHORT-COUPLED VARIANT TORSADE DE POINTES

Short-coupled variant of torsade de pointes (SCV-TdP) is an uncommon type of polymorphic ventricular tachycardia with unknown etiology. It is triggered by premature ventricular complexes with remarkably short coupling interval (<300 ms), in the absence of QT prolongation and structural heart disease

Absence of QT prolongation after administration of a 24-mg bimodal-release ondansetron pill (RHB-102).

Prospective data evaluating the effect of ondansetron on the corrected QT (QTc) interval is lacking in emergency department clinical use. As part of a randomized trial of a 24-mg bimodal-release ondansetron (RHB-102) pill, we tested the effect of RHB-102 compared to placebo on QTc change. This was a planned safety outcome analysis within a multicenter, double-blind, placebo-controlled trial. The trial compared the effects of RHB-102 among patients ≥12years who presented to 21 centers with symptoms of acute gastroenteritis. Patients with an initial baseline electrocardiogram as well as a follow-up electrocardiogram 4h later were included in the analysis. The safety endpoint for this analysis was the change from baseline in QTc interval at 4h, the median time at which ondansetron serum level peaks. A total of 147 patients were included with a mean baseline QTc in the RHB-102 and placebo arms of 410 and 406ms, respectively. There was no difference in the change in QTc at 4h post-study drug administration between the RHB-102 (+4, 95% CI 1-8ms) and placebo group (+5, 95% CI 1-9ms). In the RHB-102 arm, 6.6% of patients had a QTc change >30ms and in the placebo arm 3.6% (p=0.48). No patient in either arm had a QTc change >60ms after study drug administration. In patients with normal baseline QTc, 24-mg bimodal-release ondansetron did not prolong the QTc in comparison to placebo.

Concentration-QT Modeling Following Inhalation of the Novel Inhaled Phosphodiesterase-4 Inhibitor CHF6001 in Healthy Volunteers Shows an Absence of QT Prolongation.

Concentration‐QTcF data obtained from two phase I studies in healthy volunteers treated with a novel phosphodiesterase‐4 inhibitor currently under development for the treatment of chronic obstructive pulmonary disease were analyzed by means of mixed‐effects modeling. A simple linear mixed‐effects model and a more complex model that included oscillatory functions were employed and compared. The slope of the concentration‐QTcF relationship was not significantly greater than 0 in both approaches, and the simulations showed that the upper limit of the 90% confidence interval around the mean ΔΔQTcF is not expected to exceed 10 ms within the range of clinically relevant concentrations. An additional simulation study confirmed the robustness of the simple linear mixed‐effects model for the analysis of concentration‐QT data and supported the modeling of data obtained from studies with different designs (parallel and crossover).

Randomized, Controlled, Thorough QT/QTc Study Shows Absence of QT Prolongation with Luseogliflozin in Healthy Japanese Subjects.

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.

Does Mercury Contamination Offset the Beneficial Cardiac Effects of Increased Omega-3 Fatty Acid Intake in Avid Seafood Consumers?

Background: Fish consumption reduces risk of heart attack and cardiac death but the roles of nutrients and contaminants in fish, such as omega-3 polyunsaturated fatty acids (n-3 PUFAs) and mercury (Hg), are less clear. Increased heart rate variability (HRV) and the absence of QT prolongation (QTc) are associated with decreased cardiac mortality. Prior studies suggest that Hg and n-3 PUFAs have opposite effects on HRV, but few studies have accounted for both variables simultaneously. Aims: We investigated relationships between blood levels of n-3 PUFAs, Hg, QTc, and HRV in a cohort of 94 avid seafood consumers on Long Island, NY, USA. Methods: Fasting blood samples were collected and analyzed for Hg and n-3 PUFAs. n-3 PUFAs were defined as EPA + DHA (eicosapentaenoic acid and docosahexaenoic acid). HRV and QTc were measured in a supine position using a 10-minute Holter monitor. SDNN is the standard deviation of the interval between normal heart beats. Lower SDNN indicates reduced heart rate variability. The QT interval reflects the speed at which the heart electrically recovers after contraction. QT was averaged over the recording and corrected for heart rate using the Bazett method (QTc). Results: Median blood Hg=5.16, max = 51.0 µg/L; median EPA+DHA=4.38, max = 10.91% of FAs; median SDNN=46.84, max =164.06 ms; median QTc = 419.9, max = 491.4 ms. In linear regression models including age, sex, selenium, Hg, and EPA+DHA, neither Hg (ß= -0.006; p=0.36) nor EPA+DHA (ß= -0.035; p=0.23) were associated with SDNN. Hg-EPA+DHA interaction terms were also not significant (ß=0.002; p=0.31). No associations were found between Hg, EPA+DHA, and QTc. Frequency of fish consumption was nonsignificantly positively associated with SDNN and QTc. Conclusions: No associations were detected between SDNN or QTc and Hg, n-3 PUFAs, or fish intake. The beneficial cardiac effects of increased n-3 PUFA intake among avid seafood consumers may be offset by adverse effects of Hg contamination.

Epilepsy Misdiagnosed as Long QT Syndrome: It Can Go Both Ways

Cardiogenic seizures are common and could be the sentinel event heralding the presence of congenital long QT syndrome (LQTS). Distinguishing a cardiogenic seizure from a neurogenic one is of the utmost importance. Herein, we present the case of a 12-year-old boy with recurrent episodes of syncope and seizures. Despite absence of QT prolongation on electrocardiogram, absence of documented arrhythmias, a negative LQTS genetic test, and recurrent episodes while on nadolol beta-blocker therapy, he was diagnosed with LQTS and implanted with an implantable cardioverter defibrillator (ICD). When syncope and seizure occurred with normal sinus rhythm documented on the ICD, he was referred to neurology, and an electroencephalogram was positive for numerous bursts of bilaterally synchronous generalized discharges. He was started on antiepileptic treatment after which his seizures resolved. His LQTS diagnosis was removed, beta-blocker therapy discontinued, and his ICD was explanted. He has been seizure-free for over 2 years.

A case of electrical storm in a patient with short-coupled variant of torsade de pointes

Short-coupled variant of torsade de pointes (TdP) is an uncommon variant of polymorphic ventricular tachycardia with unknown etiology. It is initiated by a closely coupled premature ventricular complex (<300 ms) in the absence of QT prolongation and structural heart disease. Verapamil seems to be the only drug able to suppress the arrhythmia but, as it does not reduce the risk of sudden death, implantation of a cardioverter-defibrillator (ICD) is recommended. We describe the case of a 46-year-old woman referred to our Emergency Department because of palpitations. The initial ECG showed a non-sustained polymorphic ventricular tachycardia with a borderline QTc interval (450 ms). After admission, the patient experienced an episode of TdP that started after short-coupling interval (280 ms) between the last sinus beat and the ventricular premature beat (VPB). DC-shock restored sinus rhythm. Physical examination, exercise testing, echocardiography and cardiac magnetic resonance were all normal, and she had no family history of sudden cardiac death. Baseline ECG showed sinus rhythm and unifocal VPBs with the same morphology of the VPB of TdP. The patient received an ICD and was treated medically with verapamil. She was discharged from the hospital on oral therapy with verapamil (240 mg/day), and she was free of recurrence 12 months later when an electrical storm occurred. The verapamil dose was therefore increased to 480 mg/day. Unifocal VPBs disappeared from her body surface ECG, and the subsequent 3-year follow-up was uneventful.

QT prolongation is an unreliable predictor of ventricular arrhythmia

Not all drugs that prolong the QT interval are proarrhythmic, and absence of QT prolongation is no guarantee for lack of proarrhythmia. Thus, QT prolongation is an unreliable predictor of ventricular arrhythmia. Development of drugs based on the absence of QT prolongation may stop development of some of the safest agents (with respect to arrhythmias). Conversely, drug-induced shortening of the QT interval may facilitate reentry, which might have lethal consequences in vulnerable patients. If QT prolongation and QT shortening must be avoided, then the pharmaceutical industry faces a mission impossible. Cardiac safety is better evaluated in terms of lambda, TRIaD (Triangulation, Reverse use dependence, Instability, and Dispersion), and disturbances of automaticity.

A case of short-coupled variant of torsade de pointes characterized by spatial heterogeneity of action potential duration and its restitution kinetics

A 21-year-old male experienced frequent episodes of polymorphic ventricular tachycardia (PVT) initiated by a closely coupled premature ventricular complex (PVC) in the absence of QT prolongation and structural heart disease. Programmed stimulation at right ventricular apex (RVA), but not at the outflow tract (RVOT), provoked PVT degenerating into ventricular fibrillation (VF). Monophasic action potential duration (MAPD) was significantly shorter at RVA than RVOT. The maximum slope of MAPD restitution was much steeper at RVA than RVOT (1.91 versus 0.50). Such spatial heterogeneities of MAPD and its restitution may facilitate wavebreak and functional reentry predisposing to PVT and VF.

Hemodynamic effects of duloxetine at supratherapeutic dosages

Background/Aims Hemodynamic effects of duloxetine, a potent dual inhibitor of serotonin and norepinephrine uptake, were evaluated in a study designed to definitively establish the absence of QT prolongation at supratherapeutic exposures. Methods Vital signs were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy women aged 19–74 years. Duloxetine dosages escalated from 60 mg BID to 200 mg BID. Supine and postural vital signs were monitored at baseline, prior to morning dosing, and at steady state. Results Initiation of duloxetine at 60 mg BID caused a 5–7 mmHg increase in supine systolic and diastolic blood pressures that remained stable despite continued dose-escalation. Supine heart rate also increased upon dosing with duloxetine 60 mg BID, but the increase was more gradual and dose-dependent, reaching 10–12 bpm above baseline levels by the end of the 200-mg BID dosing period. Dose-dependent postural changes occurred with duloxetine, which increased throughout dose escalation. Of 11 subjects who met predefined criteria for outliers, only 5 had associated symptoms. All vital signs returned to normal by 1–2 days after stopping the drug. Conclusions Supratherapeutic duloxetine exposures produce minor and generally asymptomatic changes in supine and postural vital signs. Some prehypertensive subjects may become hypertensive upon initial dosing with duloxetine, but this can be predicted from predose values. Clinical Pharmacology & Therapeutics (2005) 77, P27–P27; doi: 10.1016/j.clpt.2004.11.104

Torsades de pointes secondary to intravenous haloperidol after coronary bypass grafting surgery

Postoperative delirium occurs in about 2% of patients undergoing major cardiac surgery including coronary artery bypass grafting surgery (CABG). Haloperidol (Sabex, Boucherville, Canada) is a drug commonly used in the intensive care unit for the treatment of delirium and is usually considered safe even at high doses and is rarely implicated in the development of malignant ventricular arrhythmias such as torsades de pointes. The purpose of this study is to report such a complication of use of haloperidol after myocardial revascularization. The patient reported underwent uneventful triple bypass surgery. Administration of large intravenous doses of haloperidol was necessary for control of psychomotor agitation due to delirium. Torsades de pointes occurred in the absence of QT prolongation on the third postoperative day following use of the drug with no other obvious etiological factor. Awareness of this rare complication is key to judicious use of this drug in the post CABG patient in whom such an arrhythmia may have very deleterious consequences because of the underlying cardiac condition.

Increased QT dispersion in the absence of QT prolongation in patients with Behcet's disease and ventricular arrhythmias

In Behcet's disease, prominent clinical manifestations include involvement of mucocutaneous, ocular, gastrointestinal, respiratory, neurologic, urogenital, articular and cardiovascular systems. Patients with Behcet's disease have higher incidence of ventricular arrhythmia than healthy subjects. However there is a little information about the mechanism of ventricular arrhythmias in Behcet's disease. The aim of the study was to investigate whether dispersion of ventricular repolarisation was an arrhythmogenic mechanism. QT dispersion parameters were measured in 73 Behcet patients and QT dispersion was defined as the difference between the maximum and minimum QT interval in any of the 12 leads of surface electrocardiogram. Corrected QT dispersion for heart rate was calculated by Bazett's formula. The results were compared with the data from 51 matched controls without a history of cardiac disease. We found QT dispersion was greater in Behcet patients (58±12 vs. 37±8 ms, P=0.001) as was corrected QT dispersion (81±14 vs. 52±11 ms, P=0.001). There was no significant difference in minimum or maximum QT intervals between Behcet patients and controls ( P>0.05). We found a correlation between QT dispersion and grade of premature ventricular complexes ( r=0.7, P=0.002). Our findings suggest that increased dispersion of repolarisation may account for the development of ventricular arrhythmias in Behcet's disease.

Increased dispersion of refractoriness in the absence of QT prolongation in patients with mitral valve prolapse and ventricular arrhythmias

Increased dispersion of refractoriness in the absence of QT prolongation in patients with mitral valve prolapse and ventricular arrhythmias

Increased dispersion of refractoriness in the absence of QT prolongation in patients with mitral valve prolapse and ventricular arrhythmias.

The mechanism responsible for the reported high incidence of ventricular arrhythmias in mitral valve prolapse is not clear. Electrocardiographic studies show an increased occurrence of repolarisation abnormalities on the 12 lead surface electrocardiogram, indicating regional differences in ventricular recovery. The purpose of this study was to investigate whether dispersion of refractoriness was an arrhythmogenic mechanism. QT dispersion was measured in 32 patients with echocardiographically documented mitral valve prolapse and ventricular arrhythmias on 24 hour Holter recordings. QT dispersion was defined as the difference between the maximum and minimum average QT interval in any of the 12 leads of the surface electrocardiogram. QT dispersion corrected for heart rate was calculated by Bazett's formula. The results were compared with the data from 32 matched controls without a history of cardiac disease. Patients taking drugs that influence the QT interval and patients with a QRS duration > 120 ms were excluded. QT dispersion was greater in patients with mitral valve prolapse than in matched controls (60 (20) v 39 (11 ms) respectively, P < or = 0.001) as was corrected QT (64 (20 ms) v 43 (12 ms) respectively, P < or = 0.001). There was no significant difference in minimum or maximum QT intervals between the two groups. QT dispersion on the 12 lead surface electrocardiogram was greater in patients with mitral valve prolapse with ventricular arrhythmias than in normal controls, but the maximum QT interval was not increased. The results accord with the hypothesis that regional shortening and lengthening of repolarisation times in patients with mitral valve prolapse may account for the increased dispersion of refractoriness.