Early Investigation of QTc Liability
- 1 September 2012
- journal article
- review article
- Published by Springer Science and Business Media LLC in Drug Safety
- Vol. 35 (9), 695-709
- https://doi.org/10.1007/bf03261967
Abstract
The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints. We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study. Among the main advantages of this approach are the ability to study the ECG effects of a wide range of doses to the maximum tolerated doses, eliminating routine analyses at unnecessary timepoints, making early go-no-go decisions, making phase II studies more efficient and, if necessary, being able to implement rigorous ECG monitoring in populations and pivotal studies of regulatory interest. If clear evidence for the presence or absence of QTc effect is found, the data from a modified MAD study may support a request for a waiver from the requirement to conduct a TQT study. In the event that a TQT study is considered unnecessary, there are obvious significant savings without compromising collection of vital safety data.Keywords
This publication has 40 references indexed in Scilit:
- Optimal Sample Size Allocation in a Thorough QTc StudyDrug Information Journal, 2011
- Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug developmentBritish Journal of Pharmacology, 2010
- The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidanceBritish Journal of Pharmacology, 2010
- Thorough QT StudiesDrug Safety, 2010
- Assessment of QTc-prolonging potential of BX471 in healthy volunteers. A ‘thorough QTcstudy’ following ICH E14 using various QT correction methodsBritish Journal of Clinical Pharmacology, 2009
- Testing for Positive Control Activity in a Thorough QTc StudyJournal of Biopharmaceutical Statistics, 2008
- Performance Characteristics for Some Typical QT Study Designs Under the ICH E‐14 GuidanceThe Journal of Clinical Pharmacology, 2008
- Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory ReviewThe Journal of Clinical Pharmacology, 2008
- Stereoselective halofantrine disposition and effect:concentration-related QTc prolongationBritish Journal of Clinical Pharmacology, 2001
- Pharmacokinetics and pharmacodynamics of ()-sotalol in healthy male volunteersBritish Journal of Clinical Pharmacology, 1996