Introduction of ICH E14 Clinical Evaluation of QT Prolongation Caused by Non-Antiarrhythmic Drug: Q&As (R3) / 药物评价研究

To detect and determine the QT interval prolongation caused by non antiarrhythmic drugs,ICH released the E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs and released E14's questions and answers (ICH E14 Q&As) in 2008 which explained some specific questions.Subsequently,This Q&As were revised third times and in June 2017 forwarded by FDA.The number of questions and answers in the revised edition doubled compared with the original.This article introduces the details of this revised edition,and hopes to be helpful to the research and supervision in China.

Medicamentos que podem induzir prolongamento do intervalo QT utilizados por idosos em domicílio / Medications that can induced QT prolongation used by elderly at home

O intervalo QT (iQT), parâmetro eletrocardiográfico, é um biomarcador não invasivo da repolarização ventricular. O aumento do iQT é uma alteração que pode ser de considerável importância clínica, pois predispõe a torsade de pointes e morte cardíaca súbita. O objetivo do presente trabalho é identificar os medicamentos utilizados em domicílio por idosos, que podem induzir o prolongamento do iQT. Trata-se de um estudo quantitativo descritivo exploratório e retrospectivo, realizado em um hospital público de ensino. Foram incluídos 190 idosos com informação sobre uso domiciliar de medicamentos registrada em prontuário. A mediana da idade foi de 69,5 anos, sendo 99 (52,1%) mulheres. O número de medicamentos utilizados por paciente em domicílio apresentou mediana de 4,0. Foram identificados 159 fármacos, sendo que 23 (14,5%) apresentavam capacidade de induzir prolongamento do iQT. Entre os idosos, 39 (20,5%) usavam estes fármacos, sendo os mais prevalentes a amiodarona, amitriptilina, nortriptilina, citalopram e fluoxetina. A hipertensão arterial foi o fator de risco mais frequente dentre aqueles que predispõem a prolongamento do iQT. As utilizações de medicamentos que induzem prolongamento do iQT e a presença de fatores de risco predisponentes mostram que os idosos estão expostos ao risco de desenvolvimento de torsade de pointes. A identificação dos fármacos que induzem prolongamento do iQT, das interações medicamentosas e das condições clínicas que predispõem a esse prolongamento são importantes para garantia da segurança da farmacoterapia de idosos e para evitar eventos adversos graves.(AU)

The QT interval (QTi), an electrocardiographic parameter, is a noninvasive biomarker of ventricular repolarization. Increased QTi is a change that may have clinical importance because predisposes to torsade de pointes and sudden cardiac death. The objective of this study was to identify drugs used by elderly at home which may induce QTi prolongation. This is a quantitative, retrospective, descriptive, exploratory study conducted in a teaching hospital. A total of 190 elderly with information on the use of medications at home available in medical records were included in the study. The median age was 69.5 years, and 99 (52.1 %) were female. The median number of medications used per patient at home was 4.0. A variety of 159 drugs were identified including 23(14.5%) that may induce QTi prolongation. Among the 39 elderly (20.5%) using drugs that may induce QTi prolongation, the most frequent were: amiodarone, amitriptyline, nortriptyline, citalopram and fluoxetine. Hypertension was the most frequent risk factor for QTi prolongation. The use of these drugs and the presence of risk factors place the elderly at increased risk for developing torsade de pointes. The identification of drugs that may induce QTi prolongation, drug-drug interactions and clinical conditions that may lead to this adverse effect reinforces the need for actions to ensure the drug safety in the elderly population and to avoid serious adverse events.(AU)

Current approaches to assess QTc prolongation for small molecule drug development / 中国药理学与毒理学杂志

Assessment of QTc prolongation is a critical step for small molecule drug development.ICH S7B continues to be the main frame to guide the assessment for this potential cardiovascular risk.The ICH guideline outlines a 3-step approach to QTc prolongation,including in vitro bERG inhibition,ex vivo action potential duration (APD),and in vivo animal telemetry approch.Dog,monkey,swine,rabbit,ferret,and guinea pig are the common laboratory animals used for in vivo electrophysiology studies,especially using conscious Beagle Dog. In addition to all these guideline standard studies,many newly developed approaches,such as receptor binding for hERG inhibition,ex vivo methods such as perfused rabbit heart or guinea pig heartare are useful models for this purpose.All these methods display good correlation to clinic outcomes,and are low cost and have rapid turn-around time in nature; so that,they can help rapidly and predict this potential cardiac liability,resulting into accelerating process for small molecule drug candidate development.