QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study

OBJECTIVE

Our aim was to assess whether severe hypoglycemic attacks were cross-sectionally associated with abnormalities of the QTc interval in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

The study included 3,248 type 1 diabetic patients from the EURODIAB IDDM Complications Study. Severe hypoglycemia was defined as an attack serious enough to require the help of another person. A corrected QTc interval (QTc) >0.44 s was considered abnormally prolonged.

RESULTS

Nineteen percent of patients declared one to two attacks, and 13.2% of patients had three or more attacks. Prevalence of QTc prolongation was greater in patients who experienced three or more hypoglycemic attacks. Logistic regression analysis showed that the frequency of severe hypoglycemia was independently associated with QTc prolongation, even after adjustment for diabetes complications, including autonomic neuropathy (odds ratio 1.27, 95% CI 1.02–1.58).

CONCLUSIONS

We have provided evidence that severe hypoglycemic attacks are independently associated with a prolonged QTc interval in type 1 diabetic patients from the EURODIAB IDDM Complications Study.Intensive glucose control increases the risk of severe hypoglycemia, and in the Diabetes Control and Complications Trial severe hypoglycemic episodes requiring assistance affected approximately one third of the intensively treated patients (1). Prolonged corrected QTc interval (QTc) reflects abnormalities of ventricular myocardial repolarization and is an independent marker of increased mortality in patients with type 1 diabetes (2). Physiologic and clinical studies have shown that provoked and spontaneous hypoglycemia induces QT lengthening (3,4). In the EURODIAB cohort, hypoglycemia was independently associated with autonomic neuropathy (5), which is common in patients with type 1 diabetes with prolonged QTc (6); however, the relationship between hypoglycemia and QTc prolongation was not explored. The aim of the current study was to assess whether severe hypoglycemic attacks were cross-sectionally associated with QTc abnormalities in this cohort.     

Pseudo-aneurysm of the anterior tibial artery, a rare cause of ankle swelling following a sports injury

Background

Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used in first-world countries and are generally well tolerated. Specifically, less cardiovascular toxicity has been reported in comparison with tricyclic antidepressants. Here we report QT interval prolongation after an overdose of the SSRI sertraline.

Case presentation

A previously healthy female patient presented with an attempted suicide with overdoses sertraline (2250 mg), diazepam (200 mg), and temazepam (400 mg). Routine laboratory studies were normal and her ECG upon admission showed a normal QT interval. The next day, her ECG showed prolongation of the QT_c interval up to 525 ms. After discontinuation of sertraline the QT interval normalized. Echocardiography and exercise electrocardiography were normal. After hospitalization, the patient resumed sertraline in the normally recommended dose and QT interval remained within normal ranges.

Conclusion

It seems that the SSRI sertraline in overdose may cause QT interval prolongation.     

Corrected QT-interval prolongation and variability in intensive care patients

Purpose

Critically ill patients are at risk for prolongation of the interval between the Q wave and the T wave in the electrocardiogram (corrected QT [QTc]). Corrected QT prolongation is probably a dynamic process. It is unknown how many patients have a QTc prolongation during their intensive care stay and how variable QTc prolongation is.

Materials and Methods

In a prospective cohort study, continuous 5-minute QTc measurements of 50 consecutive patients were collected. A prolonged QTc interval was more than 500 milliseconds for at least 15 minutes. The QT variance and variability index was used to evaluate QTc variation.

Results

Fifty-two percent of included patients had a prolonged QTc interval. In a single patient, 0.2% to 91.3% of the QTc intervals over time were prolonged. The use of erythromycin and amiodarone was associated with the mean QTc (P = .02 and P = .006, respectively). The Acute Physiology and Chronic Health Evaluation IV and Sequential Organ Failure Assessment scores were significantly higher in patients with a prolonged QTc interval (30.8 vs 8.6 and 7 vs 5.5, respectively). Eighty-four percent of all patients received at least 1 QTc-prolonging drug. The QT variance and QTc variance were significantly higher in patients with a prolonged QTc (P = .019 and P = .001, respectively).

Conclusion

Continuous QTc monitoring showed a prolonged QTc interval in 52% of intensive care patients. Severity of illness and QT and QTc variances are higher in these patients.     

Serum concentration of eperisone hydrochloride correlates with QT interval

Background

Eperisone hydrochloride is a centrally acting muscle relaxant prescribed for muscle stiffness that acts by depressing the activities of α and γ efferent neurons in the spinal cord and supraspinal structures. Although a case of eperisone-induced severe QT prolongation had been reported, the relationship between serum eperisone concentration and QT interval remains obscure.

Objective

The aim of this study was to investigate the relationship between serum eperisone concentration and QT interval.

Methods

Four patients who overdosed on eperisone were admitted to our hospital between January 2010 and December 2011. We took simultaneous serial measurements of serum eperisone concentration and QT interval in the intensive care unit. In total, 22 measurement points were plotted for these patients. We analyzed the correlation between the serum eperisone concentration and corrected QT (QTc) interval.

Results

Three men and one woman (mean age, 50 years) overdosed on eperisone with an average dose of 3087.5 mg (therapeutic dose, 150 mg/day). The mean QTc interval at arrival was 592 ms (range, 444–825 ms), and the mean serum eperisone concentration at arrival was 1257.5 ng/mL (range, 14.5–4120.0 ng/mL). The correlation coefficient was 0.833 between serum eperisone concentration and QTc interval (P < .001).

Conclusion

Serum eperisone concentration correlates with QTc interval in patients who overdose on eperisone.     

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System

Background

QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors.

QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs

A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies.     

Assessing risk of a prolonged QT interval–a survey of emergency physicians

Background

Although QT prolongation is associated with an increased risk of torsades de pointes (TdP), it is unclear how clinicians determine risk in individual patients with prolonged QT.

Aims

To investigate physicians’ interpretation of electrocardiogram (ECG) values in patients with a prolonged QT in reference to risk of TdP.

Methods

A survey was sent to Australasian emergency physicians (EPs) to investigate interpretation of ECG data in risk assessment for TdP. The survey contained three sections: demographic information, questions on heart rate correction and six sets of ECG data which the clinician ranked from low to high risk. Risk analysis for ECG values was performed by producing histograms of the distribution of responses for each of the six sets of ECG parameters. These distributions were compared to predicted distributions based on Bazett’s corrected QT>500 ms and the QT nomogram. The QT nomogram is a recently developed method for assessing whether QT-HR pairs are associated with increased risk of TdP by plotting them to determine if they are above an at risk line—the nomogram.

Results

Of 720 surveys sent out, 249 were returned (35%). A heart rate correction was used by 90% of respondents and the median “at risk” QTc judged by EPs was 450 ms [interquartile range (IQR): 440–500 ms]. Respondents were divided as to whether bradycardia increased the risk of TdP, with equal numbers responding “no change” and “more caution”. In four of the six sets of ECG parameters, EPs had a similar risk distribution to that predicted by Bazett. For one point predicted to be high risk by the QT nomogram, there was a uniform (undecided) risk distribution by EPs.

Conclusions

EPs mainly relied on Bazett’s correction as their method of TdP risk assessment, which may be problematic for bradycardic patients.     

Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose

Objective

To develop guidelines for the management of QT prolongation after citalopram overdose, including decontamination with single-dose activated charcoal (SDAC) and cardiac monitoring.

Design

Simulation study using a previously developed pharmacokinetic-pharmacodynamic (PKPD) model which predicted the time-course of QT prolongation and the effect of citalopram dose and use of SDAC on QT prolongation.

Main measures and results

The previously developed PKPD model was used to address the following in patients following citalopram overdose: (1) Above what dose should patients be decontaminated? (2) Above what dose should patients have cardiac monitoring? (3) For what period of time should patients be monitored? The primary outcome was QT,RR combinations above an abnormal threshold as a surrogate predictor of torsades de pointes. Simulations were performed using MATLAB for an overdose patient with typical demographics: 30-year-old female with a heart rate of 79?bpm taking citalopram therapeutically. The simulations showed: (1) There was significant benefit associated with the administration of SDAC to patients following citalopram overdose ingesting >?600?mg; (2) With citalopram overdoses >?1,000?mg it was advisable to give SDAC and cardiac monitor the patient; (3) The risk of developing future abnormal QT,RR combinations was less than 1% in patients with normal QT,RR combinations up to 13?h post-dose, so the minimum monitoring time for citalopram overdoses >?1,000?mg should be 13?h. Recommended dose levels for intervention should be lowered in older patients and patients with tachycardia, while men are less sensitive to QT prolongation.

Conclusions

Guidelines for the management of QT prolongation after citalopram overdose were developed. We believe the model will help clinicians to decide which patients to decontaminate and monitor.     

Potential Usefulness of Early Potassium Supplementation for Preventing Severe Hypokalemia Induced by Liposomal Amphotericin B in Hematologic Patients: A Retrospective Study

Purpose

Liposomal amphotericin B (L-AMB) is an essential antifungal agent for patients with hematologic diseases; however, the drug causes severe hypokalemia at a high frequency. Meanwhile, there is little evidence regarding the risk factors for L-AMB–induced severe hypokalemia, and the prevention protocol has not been established. The goal of this study was to identify the risk factors related to severe hypokalemia induced by L-AMB in hematologic patients.

Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized,Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults

Purpose

Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated.

Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study

OBJECTIVE

Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.

RESEARCH DESIGN AND METHODS

We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.

RESULTS

At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).

CONCLUSIONS

Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.     

Drug-drug interactions contributing to QT prolongation in cardiac intensive care units

Purpose

To determine the most common drug-drug interaction (DDI) pairs contributing to QTc prolongation in cardiac intensive care units (ICUs).

Materials and Methods

This retrospective evaluation included patients who were admitted to the cardiac ICUs between January 2009 and July 2009 aged ≥ 18 years with electrocardiographic evidence of a QTc ≥ 500 ms. Patients receiving at least two concomitant drugs known to prolong the QT interval were considered to experience a pharmacodynamic DDI. Drugs causing CYP450 inhibition of the metabolism of QT prolonging medications were considered to cause pharmacokinetic DDIs. The causality between drug and QTc prolongation was evaluated with an objective scale.

Results

One hundred eighty-seven patients experienced QT prolongation out of a total of 501 patients (37%) admitted during the study period. Forty-three percent and 47% of patients experienced 133 and 179 temporally-related pharmacodynamic and pharmacokinetic interactions, respectively. The most common medications related to these DDIs were ondansetron, amiodarone, metronidazole, and haloperidol.

Conclusion

DDIs may be a significant cause of QT prolongation in cardiac ICUs. These data can be used to educate clinicians on safe medication use. Computerized clinical decision support could be applied to aid in the detection of these events.     

QTc Prolongation as a Useful Prognostic Factor in Acute Paraquat Poisoning

Background

Acute paraquat poisoning has a high mortality rate. Several prognostic factors have been proposed to predict the mortality risk of paraquat-poisoned patients. However, these prognostic factors are complex and some require a laboratory. Corrected QT (QTc) has been used as a prognostic factor in several clinical conditions, such as acute organophosphate poisoning. In addition, the measurement can be obtained in a reasonable amount of time.

Study Objectives

This study's objective was to investigate whether QTc can predict mortality in paraquat-poisoned patients.

Methods

This was a retrospective study. Potential prognostic factors such as QTc, vital signs at admission, and certain biochemistry variables were analyzed with Cox regression analyses for their ability to predict a patient's survival from paraquat poisoning.

Results

Sixty acute paraquat-poisoned patients were admitted to the emergency department during the study period. The QTc of the survival group ranged from 0.35 to 0.48 s, whereas the nonsurvivor group ranged from 0.32 to 0.63 s. The nonsurvivor group contained a higher percentage of patients with QTc prolongation (≥0.45 s) compared with the survivor group (p = 0.04). The hazard ratio of QTc prolongation for a patient's death was found to be 2.47 (95% confidence interval [CI] 1.68–5.67) in patients with a lower potassium level (<3.2 mEq/L) and 3.71 (95% CI 1.53–8.97) in patients with a higher potassium level (≥3.2 mEq/L). In addition, hyperdynamic circulation was observed upon admission of these poisoned patients.

Conclusion

QTc prolongation is a useful prognostic factor for predicting death in acute paraquat-poisoned patients. Cardiovascular collapse may occur in some paraquat-poisoned patients. Physicians can use QTc as an indicator of a patient's severity of poisoning and mortality risk.     

A randomized,double‐blind,placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced prolongation of the QT interval has the potential to cause severe, potentially fatal ventricular arrhythmias. A number of antimicrobial agents, including fluoroquinolones and macrolides, are associated with a low, but clinically significant increased risk of QT prolongation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval in healthy subjects to determine if there were any potentials for proarrhythmic effects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study found that durlobactam had a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Because durlobactam had a low risk for prolonging the QT interval alone and when co‐administered with sulbactam, clinicians should be confident in administering the combination without risk for proarrhythmic effects.     

Global T-wave Inversions with Isolated Hypomagnesemia

Background

The physiological actions of magnesium within the cardiac conduction system and myocytes have yet to be fully elucidated. Because concurrent hypocalcemia or hypokalemia were also present in previous human reports, specific electrocardiographic effects of isolated hypomagnesemia have not been clearly delineated.

Objective

We report a case in which dynamic electrocardiogram (ECG) changes were demonstrated in isolated hypomagnesemia.

Case Report

A 37-year-old man with history of heavy alcohol use was admitted for syncope. The ECG showed global T-wave inversions with prolonged corrected QT (QTc) duration on ECG. Extensive work-up including cardiac catheterization was unremarkable. His serum magnesium was noted to be low at 1.1 mg/dL, and his serum calcium and potassium were within normal limits. The patient received magnesium infusion with subsequent ECGs showing resolution of his global T-wave inversions and prolonged QTc.

Conclusion

This case is unique because it reports dynamic ECG changes in a patient with isolated hypomagnesemia. Although isolated hypomagnesemia is commonly believed to result in dysrhythmia, we were unaware of any previous cases of ECG abnormalities in humans. Clinically, we advise checking serum magnesium and correcting hypomagnesemia when prolonged QTc duration and global T-wave inversions are seen on ECG.     

Electrocardiographic findings of palonosetron in cancer patients

Purpose

Nausea and vomiting are among the major problems occurring during and after the chemotherapy treatments of cancer patients. The recently developed 5-HT₃ antagonists have proved much more effective than former agents. Several studies have shown that these agents cause certain ECG changes. We aimed to evaluate the ECG changes caused by palonosetron, one of the new 5-HT₃ antagonists.

Methods

Our study includes a total of 50 patients diagnosed with solid-organ tumors receiving chemotherapy. The patients were applied 12-lead ECG before palonosetron infusion. Afterwards, subsequent ECGs were applied on the 30th, 60th, and 90th minutes following the infusion of palonosetron. Arterial blood pressure was measured before and after the infusion. PR, QRS, QT, QTmax, QTmin, QTd, Pmax, Pmin, Pd, QTc, QTcmax, QTcmin, and QTcd values were evaluated for each ECG.

Results

We did not detect significant correlations between the systolic and diastolic blood pressures before and after (30?min) palonosetron infusion (p?>?0.05). However, there was a statistically significant decrease in heart rate (p?=?0.000). The evaluation of ECG findings revealed that there was a significant prolongation in PR distance, as shown by the comparisons of 0?min with 30, 60, and 90?min. On the other hand, there was no significant difference in QRS, QT, QTmax, QTmin, QTd, Pmax, Pmin, Pd, QTc, QTcmax, QTcmin, and QTcd values (p?>?0.05).

Conclusion

In this study, we revealed that palonosetron did not cause any severe rhythmic disorders or symptomatic ECG changes. We concluded that it could be safe to administer palonosetron antiemetically.     

Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers

Bempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double‐blind, parallel‐design clinical study assessed the effects of steady‐state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half‐maximal inhibition (IC₅₀) estimated at greater than 1000 μM (>1670‐fold the bempedoic acid 180 mg/day steady‐state unbound maximum concentration). In monkeys, individual rate‐corrected QT intervals showed no time‐ or dose‐dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia’s formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration‐QTcF analysis showed that maximum bempedoic acid concentration at steady‐state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was −0.5 (−5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady‐state bempedoic acid at a supratherapeutic dose of 240 mg was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced QT prolongation is associated with a rare and potentially fatal ventricular arrhythmia known as torsades de pointes. As a result, it is now a standard regulatory requirement for drug candidates to undergo assessment of QT prolongation risk.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Bempedoic acid is an inhibitor of adenosine triphosphate (ATP)–citrate lyase that is chronically administered to patients at risk for or with cardiovascular disease for the treatment of hypercholesterolemia. This phase I study assessed whether steady‐state concentrations of bempedoic acid at a supratherapeutic dose of 240 mg is associated with increased risk of prolongation of ventricular repolarization.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study demonstrated that steady‐state concentrations of bempedoic acid and its active metabolite {"type":"entrez-protein","attrs":{"text":"ESP15228","term_id":"556126718"}}ESP15228 were not associated with QT/QTc interval prolongation in 54 healthy subjects who received bempedoic acid 240 mg once daily for 9 days. This study adds supportive cardiac safety information for the safe and efficacious use of bempedoic acid in patients with cardiovascular disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In vitro human ether‐a‐go‐go–related gene (hERG) binding and results in cynomolgus monkeys indicated that bempedoic acid has a favorable cardiac electrocardiographic nonclinical safety profile. These nonclinical results are consistent with the findings of a clinical study in which bempedoic acid at a supratherapeutic dose level was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.     

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Typical cardiovascular studies usually employ timepoint analysis. Published in vivo corrected QT (QTc) assay data has exhibited variability in QTc sensitivity that results in challenges in nonclinical‐clinical assessment of translation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Comparison of nonclinical timepoint and concentration QTc (C‐QTc) analyses and how it relates to clinical moxifloxacin data.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Dog and non‐human primate (NHP) QTc timepoint and C‐QTc analyses detect QTc internal prolongation, have equivalent sensitivity, and improve confidence in these models for proarrhythmic risk mitigation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Risk assessment in nonclinical models translates well to human thorough QT (TQT) data for moxifloxacin. The new data highlights the value of a high‐quality dog or NHP QTc assay to support clinical risk assessment and regulatory decision making.