ICH E14: A New Regulatory Guidance on the Clinical Evaluation of QT/QTc Internal Prolongation and Proarrhythmic Potentia
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Philip 1. Sager, MD, FACC, FAHA Cardiovascular Research, AstraZeneca LP, Wilmington, DE, and Clinical Professor of Medicine, University ofMedicine and Dentishy NewJersey, USA
Thierry Nebort, MD Medical Sciences, Institut de Recherches Internationales SERVIER, Pans, France Borie Darpo, MD, PhD, FACC Daiichi Medical Research. Montvale, New Jersey, USA, and Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
Key Words 1CH E14; Torsade de pointes; Proarrhythmia; Thorough QT study Correspondence Address Philip T.Sage MD, FACC, FAHA, AstraZeneca LP, Clinical Professor of Medicine, UMDNJ-New Jersey School ofMedicine, 1800 Concord Pike, C3B526, Wilmington, DE 19850-5437 (email: Philip.Sager@AstraZeneca. corn).
‘The aim ofthis article is to give a summary of the International Conference on Harmonisation (ICH) E 14 document as it stands after having reached step 4 in Brussels, Belgium. May 2005. The authors are representatives for the pharmaceuticalindustry in the United States (Pharmaceutical Research and Manufacturers of America [PhRMA]; PTS) and Europe (European Fedemtion of Pharmaceutical Industries and Asson’ations [EFPIA]; BD and TN) on the Expert Working Group for this document. Interpretations of some recommendations given in E 14 may differ in regions (European Union, United States, Japan), and the opinions expressed in this article are those ofthe authors and do not necessarily reflect the views of the ICH Expert Working Group, PhRMA, or EFPIA or individualpharmaceutical companies.
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ICH E14: A New Regulatory Guidance on the Clinical Evaluation of QT/QTc Internal Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs* INTRODUCTION The polymorphic ventricular tachycardia torsade de pointes (TdP) has been identified as a significant health care problem because it may be precipitated by non-antiarrhythmic medications that prolong ventricular repolarization and the QT interval (1-3). This ventricular tachycardia is typically rapid (>175 beats per minute) and may result in presyncope, syncope, or, when sustained, sudden cardiac death. QT prolongation and TdP are the second most common reasons for medications to lose their marketing approval or to have significant restrictions placed on their clinical use (4,5). Some of the drugs that have recently been affected include terfenadine, astemizole, cisapride, droperidol, grepafloxacin, levomethadyl, lidoflazine, sertindole, and terodiline. In addition, the observation of QT prolongation on the electrocardiogram during drug development has resulted in the denial or delay of marketing approval for a number of pharmacologic agents. This issue was highlighted in the early 1990s when it was observed that terfenadine treatment for allergic rhinitis was associated with the development of sudden cardiac death from TdP, including young people without heart disease (1,6). Typically, individuals who obtained high plasma concentrations resulting from reduced clearance (eg, by inhibition of the cytochrome P450 system by drugs or g
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