Proarrhythmic potential

El 4 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Pharmacogenomics... 

ICH Topic E14-The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. EMEA.(2005) http //emea.eu.int/pdfs/human/ich/ 000204en.pdf. (last accessed 2/25/2007). 

Thomsen, M.B., Matz, J., Volders, P.G. and Vos, M.A. (2006) Assessing the proarrhythmic potential of drugs current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacology el Therapeutics, 112, 150-170. 

Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline. Journal of Clinical Pharmacology, 46, 498-507. 

ICH E14 Note for Guidance on the Clinical Evaluation of QT/ QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs Provides recommendations concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to slow cardiac repolarization Anon.53... 

Valentin, J.P., Hoffmann, P., De Clerck, F., Hammond, TG. and Hondeghem, L. (2004) Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. Journal of Pharmacological and Toxicological Methods, 49, 171-181. 

ICH (2005) E14 the dinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 

Why The FDA is interested in having access to ECG waveform data collected during the course of definitive studies on drug effects on ventricular repolarization and annotated for interval measurements. The basis for this interest is described in detail in the concept paper The Clinical Evaluation of QT Interval Prolongation and Proarrhythmic Potential for Non-antiar-rhythmic Drugs, jointly authored by the U.S. and Canadian regulatory authorities and discussed at a joint FDA/DIA meeting in January 2003. 

The clinical evaluation of QT/QTc interval prologation and proarrhythmic potential for nonantiarrhythmic drugs. FDA DRAFT preliminary concept paper. Nov. 15, 2002... 

Carlsson L, Amis GJ, Andersson B et al. (1997) Electro-physiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro Implications for proarrhythmic potential J Pharmacol Exp Ther 282 220-227... 

Studenik et al. (1999) used isolated spontaneously beating Purkinje fibers from guinea pigs to study the proarrhythmic potential of antidepressant and neuroleptic drugs. 

The M cell is a unique myocardial cell type found in the deeper layers of the ventricular wall (Antzelevitch et al. 1999). These cells respond more sensitively to agents that block hERG channels and, as such, contribute to possible drug-induced transmural heterogeneity of ventricular repolarization and thereby the proarrhythmic potential. The perfused myocardial wedge preparation is design to allow the study of transmural differences in drug action on the action potential and may therefore provide a better assessment of possible proarrhythmic potential of a test article. 

In contrast, amiodarone and sotalol are effective in most supraventricular and ventricular tachycardias. Amiodarone displays electrophysiologic characteristics consistent with each type of antiarrhythmic drug, ft is a sodium channel blocker with relatively fast on-off kinetics, has nonselec-tive j8-blocking actions, blocks potassium channels, and has slight calcium antagonist activity. The impressive effectiveness and low proarrhythmic potential of amiodarone have challenged the notion that selective ion channel blockade is preferable. Sotalol is a potent inhibitor of outward... 

CDER, CBER. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Preliminary Concept Paper, Rockville FDA 2004. (Internet at http // www.fda.gov/cder/guidance/index.htm.)... 

A delay of the ventricular transmural repolarization is an important component to define the proarrhythmic potential of a drug. The milder the delay of transmural repolarization is, the lower the likelihood of developing proarrhythmic events is. 

Several new developments on QT/QTc prolongation assessment have occurred recently. The most important includes the publication of the new International Conference of Harmonisation (ICH), Step 4 guidance, issued on May 12, 2005 entitled The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. It contains relevant information obtained from the ICH Steering Committee, as well as information discussed at the Qctober 2003 Food and Drug Administration (FDA) and Drug Information Association (DIA)... 

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