全面QT/QTc研究、药物浓度QTc研究与心脏安全

非抗心律失常药物特别是抗肿瘤药物会影响心脏复极化,进而延长QT间期,导致患者出现恶性心律失常,发生心源性猝死.近年来,此类药物不良反应越来越受到监管部门、药物研发企业以及临床医生的关注.随着《E14:非抗心律失常药物QT/QTc间期延长及致心律失常潜力的临床评价》和《S7B:人用药品延迟心室复极化(QT间期延长)潜在作...     

药物心脏安全性评估与全面QT/QTc研究

许多非抗心律失常药物可以导致心电图QT间期延长,甚至引发尖端扭转型室性心动过速.因此在新药上市前,进行的心脏安全性评估,应该包括药物对QT间期影响的特点.全面QT/QTC研究旨在通过测量QT间期,明确药物是否具有延长QT间期的作用,判断其引发恶性心律失常的风险,并为决定药物是否进入下一步研发提供数据支持.     

1439例药源性心律失常自发报告分析

摘要：目的:了解药源性心律失常的发生规律及特点,为临床安全用药提供参考。方法:采用回顾性研究方法,提取我中心药品不良反应数据库中2008～2019年药源性心律失常的自发报告,剔除信息不全和无效报告后对报告一般情况、患者基本信息、药物类别、给药途径、心律失常类型、ADR治疗和转归等情况进行统计分析。利用Logistic回归分析方法筛选相关风险因素。结果:1 439例药源性心律失常报告中,患者平均年龄为（55.17±21.20）岁,以45～64岁占比最高（35.72%）;共涉及19类、387种药物,排名前5位的药物是右美托咪定（24.15%）、莫西沙星（16.18%）、重组人白介素-11（11.11%）、沙丁胺醇（10.39%）、胺碘酮（7.73%）;心律失常类型多样,以心动过速（56.46%）和心动过缓（19.63%）为主。与非QT/QTc间期延长组相比,年龄>65岁（P=0.007）及患有心脑血管疾病（P=0.016）是QT/QTc间期延长患者的独立危险因素;治疗药物以抗心律失常药和抗过敏药为主。结论:莫西沙星和胺碘酮可导致多种类型的心律失常,重组人白介素-11以诱发心房颤动为主,右美托咪定主要为心动过缓,临床应加强用药监护;老年人和原患心脑血管疾病是药物导致QT/QTc间期延长的高风险因素,临床应予以重点关注;有必要开展重点品种主动监测研究,为临床提供用药参考。     

抗新型冠状病毒药物致QT间期延长的文献复习及药学监护

本文对新型冠状病毒肺炎患者临床用药方案涉及的抗病毒药物致QT间期延长的文献报道情况进行复习。根据目前文献复习结果可知,洛匹那韦/利托那韦和磷酸氯喹存在引起QT间期延长进而引发尖端扭转型室速的潜在风险。在新型冠状病毒肺炎患者中使用此类药物需关注由此带来的用药风险,熟悉临床上常用的可引起QT间期延长的药物,提高识别患者QT间期延长的易感因素和药物相互作用的能力,重视心电图、电解质管理来预防临床潜在的药物致急性心律失常事件,以降低新型冠状病毒肺炎患者的药物不良反应,避免药源性损害。     

莫西沙星在全面QT研究中的应用及特点

莫西沙星作为一种新型广谱氟喹诺酮类抗菌药在临床上主要用于治疗成人呼吸道感染。该药具有明确的可导致心电图QT间期延长的作用,同时对心率影响不大,相对于其他导致QT间期延长的药物来说,其导致的心律失常及其他的不良反应较为轻微,是目前全面QT研究中最常用的阳性对照药物。本文对莫西沙星在该项研究中的应用及其QT作用的特点进行了阐述。     

胺碘酮与其他延长QT间期药物合用情况的研究

目的了解我院住院患者应用胺碘酮的同时应用其他致QT间期延长药物的现状,对其他致QT间期延长药物的重视程度及对QT间期的关注情况。以引起临床医师重视,确保用药安全。方法筛选我院近10年心律失常患者住院期间可能应用胺碘酮的病例,依据与胺碘酮同时应用致QT间期异常延长的相关报道,记录应用胺碘酮的病历医嘱中是否存在合并用药,合并用药种类,合并用药前后QT间期及QTc间期延长情况,统计单独应用胺碘酮病例数,合并应用其他致QT间期延长药物病例数,合并用药占相关疾病的比例,有无尖端扭转室速及死亡事件发生。病程中提及胺碘酮合并用药致QT间期延长相关内容的例数。结果共收集83份应用胺碘酮治疗的住院患者的病例。合并应用其他致QT间期延长药物有4种,分别为非洛地平(9例,11%)、硝苯地平(7例,8%)、左氧氟沙星(3例,4%)及多潘立酮(4例,5%)。其中单独应用胺碘酮者62例,合并应用其他致QT间期延长药物者共21例,包括合并应用一种药物者(19例,23%),两种药物者(2例,2%)。应用胺碘酮病例无死亡事件。所研究病例的病程记录中均未提及应用胺碘酮及合并用药时要注意观察QT间期的相关内容。结论我院住院患者中应用胺碘酮时,对合用其他致QT间期延长药物的重视程度还不够,应重视心电图QT间期及QTc间期的变化,避免尖端扭转室速等致命性心律失常的发生,以确保用药安全。     

止吐剂昂丹司琼有心律失常风险

2011年9月,美国FDA就正在进行的止吐剂昂丹司琼（ondansetron/Zofran等）安全性审查和标签更改事项发出通知：昂丹司琼可能延长心电图QT间期,这可能导致产生异常和潜在致命的心律失常、包括尖端扭转型室性心动过速。那些有潜在心脏疾病（如先天性长QT综合征）、血液中钾和镁水平较低或正在服用可能引起QT间期延长的其它药物的患者出现尖端扭转型室性心动过速时特别危险。     

ICH E14《非抗心律失常药所致QT延长临床评价:问答第3次修订版》介绍

为了发现并判断非抗心律失常药所致的QT间期延长,人用药品技术要求协调国际会议（ICH）发布了E14《非抗心律失常药致QT/QTc间期延长及潜在致心律失常作用的临床评价指导原则》。2008年ICH发布了该指导原则的问答（E14 Q&As）,对一些具体问题做了说明,随后又对问答做了第3次修订,问答数较原版增加了1倍。美国食品药品管理局（FDA）于2017年6月对第3次修订版予以转发。介绍该修订版的详细内容,希望对我国非抗心律失常药临床评价相关方面的研究和监管工作有益。     

药物导致的获得性长QT综合征诊断与治疗

药物导致的获得性长QT综合征是由药物引起的可逆性的QT间期延长的综合征,其主要机制是药物通过对IKr的阻断作用,导致动作电位3期快速复极延迟,表现为QT间期延长。在临床上,许多结构上无关的药物,包括抗精神病药物均可以导致QT间期的延长。药物导致的获得性长QT综合征容易导致尖端扭转性室性心动过速（TdP）,临床上可以通过Tp-e和Tp-e/QT比值、巨大T-U波、QRS缓慢上升支和QT间期短期变异可以预测TdP的风险。治疗获得性长QT综合征,最根本的是识别和停用导致QT间期延长的药物并积极的纠正代谢异常,如低钾血症或低镁血症。大多数TdP的发作是短暂的,并可自行终止。然而,长时间发作会导致血流动力学紊乱,需要立即进行电复律。     

麻醉药物与围术期心电监测

摘要：心电监测是围术期患者必不可少的监测项目,可协助麻醉医生实施高效的麻醉管理与麻醉规划,其具有的及时、个体化、显著、易于识别等优势还可用于指导麻醉用药方案。围术期心电监测结果受到多种因素的影响,术中麻醉药物对心电图的影响也多种多样。局部麻醉药物引起PQ间期延长、QRS波延长、HR减慢,布比卡因可导致心律失常发生率升高;瑞芬太尼引起HR减慢、PR间期、QRS时限和QTc间期缩短,大剂量时造成心肌显著抑制,舒芬太尼仅引起HR减慢;氯胺酮导致HR增快、RR间期延长、QRS间期延长;非甾体抗炎药引起ST-T改变与R波脉搏波传导增快;丙泊酚诱导时引起HR减慢、Tp-e与QTc间期延长;硫喷妥钠引起QTc间期明显延长、HR升高;右美托咪定导致HR明显减慢、QT间期延长、QTc间期缩短与Tpe/QT比值减小;琥珀胆碱引起HR减慢,发生严重高钾血症时出现QT间期缩短、QRS波增宽等;阿曲库铵、罗库溴铵、米库氯铵、泮库溴铵与氧化亚氮均引起HR增快;新斯的明和舒更葡糖钠均引起HR减慢,舒更葡糖钠还可导致QT间期延长;高浓度七氟烷引起HR减慢、QTc间期延长与Tp-e/QT比值降低;异氟烷、地氟烷均可引起HR增快、QTc间期延长;氟烷可引起HR减慢、QTc间期延长。     

Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women

AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.     

Bias and Variance Evaluation of QT Interval Correction Methods

There is an increasing regulatory emphasis on assessing drug-induced QT interval prolongation. Since QT interval is correlated with heart rate (HR), assessment of drug-induced QT interval prolongation should be made at a standardized HR, resulting in the need to correct QT interval (QTc) for HR. This study investigates the statistical properties of QTc intervals using individual based correction (IBC), population based correction (PBC), or fixed correction (FC) methods under both the linear and log-linear regression models for the QT–RR relationship where RR is the time elapsing between two consecutive heart beats (inversely related to HR through RR = 60/HR). This study shows that QTc intervals using PBC and FC methods are conditionally biased. The QTc interval using the IBC method is conditionally unbiased under the linear regression model, but is conditionally biased under the log-linear regression model. It also shows that under both the linear and log-linear regression models, the conditional variances of the QTc intervals using the three correction methods satisfy the order FC ≤ PBC ≤ IBC. Suggestions for analyzing QT intervals based on these findings are discussed.     

Quantitative Relationship Between Myocardial Concentration of Tacrolimus and QT Prolongation in Guinea Pigs: Pharmacokinetic/Pharmacodynamic Model Incorporating a Site of Adverse Effect

Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration–response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (E_max) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The E_max model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.     

Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes

BACKGROUND AND PURPOSE: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. EXPERIMENTAL APPROACH: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. KEY RESULTS: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. CONCLUSION AND IMPLICATIONS: STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.     

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

In this review, factors affecting the QT interval and the methods that are currently in use in the analysis of drug effects on the QT interval duration are overviewed with the emphasis on (population) pharmacokinetic-pharmacodynamic (PK-PD) modeling. Among which the heart rate (HR) and the circadian rhythm are most important since they may interfere with the drug effect and need to be taken into account in the data analysis. The HR effect or the RR interval (the distance between 2 consecutive R peaks) effect is commonly eliminated before any further analysis, and many formulae have been suggested to correct QT intervals for changes in RR intervals. The most often used are Bazett and Fridericia formulae introduced in 1920. They are both based on the power function and differ in the exponent parameter. However, both assume the same exponent for different individuals. More recent findings do not confirm this assumption, and individualized correction is necessary to avoid under- or overcorrection that may lead to artificial observations of drug-induced QT interval prolongation. Despite the fact that circadian rhythm in QT and QTc intervals is a well-documented phenomenon, it is usually overlooked when drug effects are evaluated. This may result in a false-positive outcome of the analysis as the QTc peak due to the circadian rhythm may coincide with the peak of the drug plasma concentration. In view of these effects interfering with a potential drug effect on the QTc interval and having in mind low precision of QT interval measurements, a preferable way to evaluate the drug effect is to apply a population PK-PD modeling. In the literature, however, there are only a few publications in which population PK-PD modeling is applied to QT interval prolongation data, and they all refer to antiarrhythmic agents. In this review, after the most important sources of variability are outlined, a comprehensive population PK-PD model is presented that incorporates an individualized QT interval correction, a circadian rhythm in the individually corrected QT intervals, and a drug effect. The model application is illustrated using real data obtained with 2 compounds differing in their QT interval prolongation potential. The usefulness of combining data of several studies is stressed. Finally, the standard approach based on the raw observations and formal statistics, as described in the Preliminary Concept paper of the International Conference on Harmonization, is briefly compared with the method based on population PK-PD modeling, and the advantages of the latter are outlined.     

QTc interval prolongation by d-propoxyphene: what about other analgesics?

Introduction: d-Propoxyphene, which was previously available in many single-agent and combination products, was recently voluntarily withdrawn from the US market following an FDA recommendation based partly on the concern that the risk associated with QT prolongation exceeded the clinical benefit of the drug. The drug had previously been withdrawn from European markets. These recent actions prompt the question: what is known about QT prolongation and analgesic drugs?

Areas covered: A systematic search was conducted of 50 opioid and non-opioid analgesic drugs using PubMed, the FDA website, and the Internet. Search terms for opioids, NSAIDs, acetaminophen and other analgesics were used (including both generic and brand names), along with QTc, QTc prolongation, QTc interval, hERG, torsades de pointes (TdP), ventricular arrhythmias, and other relevant terms.

Expert opinion: There is a paucity of available information on the QT interval for most analgesics. Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval.     

QT PRODACT: in vivo QT assay in anesthetized dog for detecting the potential for QT interval prolongation by human pharmaceuticals

The purpose of this study was to assess the utility of the isoflurane-anesthetized dog model for detecting the potential for QT interval prolongation by human pharmaceuticals. The effects of 10 positive compounds with torsadogenic potential, 8 negative compounds with little torsadogenic potential, and dl-sotalol as a common positive compound were evaluated in 5 facilities in accordance with the common protocol approved by QT PRODACT. Each test compound was cumulatively infused into male beagle dogs anesthetized with isoflurane. Surface lead II ECG, blood pressure, and plasma concentrations for the positive compounds were measured. Repeated administration of the vehicle examined in each facility before the start of the experiments resulted in a slight, but not significant, change in corrected QT (QTc) interval, indicating that this model only shows slight experimental variation. Although an inter-facility variability in the extent of dl-sotalol-induced QT interval prolongation was observed, dl-sotalol significantly prolonged QTc interval in all facilities. All positive compounds significantly prolonged QTc interval at plasma levels up to 10 times those in patients who developed prolonged QTc interval or TdP, whereas no negative compounds did so. These data suggest that the in vivo QT assay using the anesthetized dog is a useful model for detecting the potential for QT interval prolongation by human pharmaceuticals.     

Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in southwestern coast of Taiwan

Chronic arsenic exposure has been documented to be associated with various cardiovascular diseases. We aimed to investigate 1) the increased risk of QT prolongation in chronic arsenic exposure, and 2) the relationships of cardiac repolarization (QT interval duration) with ischemic heart disease and carotid atherosclerosis. We studied 280 men and 355 women living in the endemic area of arseniasis in southwestern Taiwan. QT intervals in electrocardiogram and carotid intima-media thickness (IMT) by ultrasonography were measured. Ischemic heart disease was diagnosed by history or abnormal electrocardiogram. Significant associations of the corrected QT interval (QTc) duration with ischemic heart disease and carotid intima-medium thickness and plaque were observed after adjustment for various risk factors in the multiple linear regression analysis (all p values < 0.05). Three indices of chronic arsenic exposure were all significantly associated with the risk of QTc prolongation showing dose-response relationships (p < 0.001). Chronic arsenic exposure was dose-dependently associated with the risk of QTc prolongation. Ischemic heart disease and carotid atherosclerosis were significantly associated with QTc intervals in chronic arsenic exposure. QTc prolongation might be suggested as an early biomarker for ischemic heart disease or carotid atherosclerosis in population with previous exposure to arsenic.