E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs — Questions and Answers (R3) Guidance for Industry

THE CLINICAL EVALUATION OF QT/QTc INTERVAL PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS

Early drug development: assessment of proarrhythmic risk and cardiovascular safety.

INTRODUCTION hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as...

Bayesian Population Pharmacokinetic/Pharmacodynamic Modeling to Study the Effect on the Cardiovascular Syndrome of the QTc Interval Prolongation of Non-antiarrhythmic Drugs

Assessment of the propensity of non-antiarrhythmic drugs in prolonging QT/QTc interval is critical for the progression of compounds into clinical development. Given the similarities in QTc response between dogs and humans, dogs are often used in pre-clinical cardiovascular safety studies. The current regulatory guidelines are based on simple statistical analyses of QT data, thereby ignoring any...

The Contribution of Early-phase Clinical Data to a Drug’s Integrated Cardiac Safety Portfolio

Cardiac adverse drug reactions are typically serious and can be fatal. Reports of sudden cardiac deaths resulting from several licensed drugs, including macrolide antibiotics, cisapride, terolidine, bepridil, and terfenadine, led to marketing withdrawals in the UK and the US in the 1980s and 1990s. These fatalities prompted concerted regulatory attention that led to the release in 2005 of ICH G...

Dose-Dependent Effects of Methadone on QT interval in Patients under Methadone Maintenance Treatment

Background: The role of methadone in QTc prolongation, Torsades de Pointes (TdP) arrhythmia and sudden cardiac death has been debated. Because of widespread use of methadone in methadone maintenance treatment (MMT) centers, we aimed to study dose-related effects of methadone on QTc prolongation. Methods: In a comparative observational study, 90 patients who were under MMT were evaluated. Patien...