Assessment Of QT Interval Prolongation Research Articles

Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 μM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

1545. Development of a Linear Mixed-Effect Pharmacodynamic Model to Quantify the Effects of Frequently Prescribed Antimicrobials on QT Interval Prolongation in Hospitalized Patients

BackgroundTorsades de pointes is a life-threatening ventricular tachycardia associated with prolongation of the QT interval. Many diseases and medications have been implicated as potentially prolonging the QT interval, but little data exists regarding the means of quantifying this risk. The aim of this study was to describe the impact of commonly used antimicrobials on the QT interval in hospitalized patients.MethodsDemographic, diseases, laboratory, medication administration history and ECG recording data were collected from the electronic records of adult patients admitted, from July 2018 to December 2018, to two urban hospitals. A model for the QT interval comprised of four sub-models: gender, heart rate, circadian rhythm, and the drug and disease effects. Fixed and random effects with between occasion variability were estimated for the parameters. A Bayesian approach using the NUTS in STAN was used via the brms package in the R® software.ResultsData from 1,353 patients were used with baseline characteristics shown in Table 1. Observed vs. predicted plots based on the training (Figure 1A) and validation data set (Figure 1B) showed a great fit. The parameters for QTc0, α, gender, and circadian rhythm were accurately identified (Table 2). Similarly, the model correctly described the expected impact of acute or chronic diseases on the QT interval. Uncertainty interval estimates (Figure 2) show that patients treated with fluconazole and levofloxacin are likely to present with a QT interval [mean (95% CI) of 6.84 (0.22,21.45) and 5.05 (0.15, 16.70), respectively], that is > 5 ms longer vs. no treatment, the minimum cutoff that should evoke further risk assessment of QT interval prolongation.ConclusionThe model developed correctly describes the impact baseline risk factors have on the QT interval. Point estimates of QT interval prolongation show that patients treated with fluconazole and levofloxacin may be at considerable risk; while those treated with azithromycin or ciprofloxacin are more likely to be at an insignificant risk for QT interval prolongation during hospital admission. Further workup to quantify the impact of concomitant treatment with these and other at-risk medications is underway. Disclosures All authors: No reported disclosures.

A Bayesian Measurement Error Approach to QT Interval Correction and Prolongation

Assessment of QT interval prolongation is an integral part of clinical studies in drug development because a prolonged QT interval can cause sudden cardiac death. Traditionally a linear or non-linear regression method is applied to estimate subject- or group-specific heart rate corrected QT intervals (QTc) on which comparisons are based among treatment groups. These regression models rely on a fundamental assumption that the predictor variable (RR interval) is measured without error. However, the fact is that both QT and RR intervals measured in electrocardiogram (ECG) are subject to not only measurement error, but also fluctuation that is caused by physiological and biological factors. Hence the assumption in the regression models is most likely violated. In this paper we propose a Bayesian hierarchical measurement error model to evaluate QTc interval and prolongation. The proposed approach is illustrated using a real data set. Simulation studies show that our proposed Bayesian measurement error approach outperforms the current most commonly used frequentist methods.

Statistical Analysis Methods For QT/QTc Prolongation

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

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n = 4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma/serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals.Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A2

A maximum likelihood approach for estimating the QT correction factor using mixed effects model.

Assessment of QT interval prolongation is often used for assessing the cardiac safety of a new drug. However, the correction of the QT interval for varying heart rates has potential bias due to various different correction factors. This article proposes a maximum likelihood (ML) approach for calculating the appropriate individual correction factor using the data. The data come from a study with 24 subjects participating in a 10 day multiple dose (NEW RX) placebo-controlled cross-over trial with repeat ECGs obtained at baseline and at day 10. ML techniques were used to fit a random-effects model to observed QT and HR values for estimating the pooled and individual correction factors. QT(c) values using four correction factors (Bazett, Friderecia, pooled and individual) were investigated. The relative performance of the various correction factors are given in terms of variability and graphical techniques. The pooled correction factor was estimated to be 0.292 and the individual correction factors ranged from 0.19 to 0.41. The assessment of the treatment effect on QT(c) yielded inconsistent results. Bazett's factor indicated prolongation (6.55+/-1.20), Friderecia's factor indicated no change, while the pooled (-2.92+/-0.94) and individual (-2.82+/-1.00) factors showed a significant decrease. Graphical examination of individual QT(c) data showed a significant advantage in the use of individual correction factors versus Bazett's factor both in terms of sensitivity as well as reduction in bias. Use of individual correction factors is advocated for the assessment of possible drug-induced QT(c) prolongation.

The dog's role in the preclinical assessment of QT interval prolongation.

During the development of a new therapeutic, few pharmacodyamic outcomes currently receive as much scrutiny as the effect of a potential medication on the electrocardiographic QT interval. The recent withdrawal from marketing of several drugs due to potential drug-related cardiac arrhythmias have greatly increased concern about drug-related changes on the QT interval. In order to reduce the incidence of these idiosyncratic episodes, regulatory agencies have suggested that sponsors use more rigorous methodology during the safety evaluation of new pharmaceuticals. Along with enhanced electrocardiographic assessments during clinical trials, advanced preclinical examinations of effect on QT interval and ventricular repolarization have become de rigueur. In this arena, the beagle dog is the preclinical species often associated with the most reliable predictivity for human safety assessment. To this end, canine models of cardiovascular safety assessment are discussed along with the relevance of these assays to human electrocardiography.

The Dog's Role in the Preclinical Assessment of QT Interval Prolongation

The Dog's Role in the Preclinical Assessment of QT Interval Prolongation

The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods

The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods

Assessment of QT interval prolongation and autonomic nervous dysfunction in patients undergoing orthotopic liver transplantation

The acu-men;™: A new device for continuous renal replacement therapy in acute renal failure.We sought to design a simple machine to safely provide continuous veno-venous hemofiltration to acute renal failure patients.The acu-men™ device uses a pneumatic blood pump with tidal blood flow as the driving force. A volumetric balancing system balances the filtrate with the replacement fluid, and the blood—air interface is eliminated by replacing the conventional venous drip chamber with two air-separating membranes. The extracorporeal circuit is integrated in a disposable cartridge, which is inserted into the machine at the beginning of treatment. The priming and rinsing is done automatically.While preliminary data from an ongoing clinical trial on the efficacy of this device are encouraging, further longer-term studies are necessary to evaluate its potential to decrease morbidity and mortality in acute renal failure patients.