Drug-induced torsades de pointes and implications for drug development.
Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.
Fenichel
Robert R
RR
Washington, DC, USA.
Malik
Marek
M
Antzelevitch
Charles
C
Sanguinetti
Michael
M
Roden
Dan M
DM
Priori
Silvia G
SG
Ruskin
Jeremy N
JN
Lipicky
Raymond J
RJ
Cantilena
Louis R
LR
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D015507:Drugs, Investigational / Q000009:adverse effects*; D004562:Electrocardiography; D004594:Electrophysiology; D006801:Humans; D008133:Long QT Syndrome / Q000503:physiopathology; D018570:Risk Assessment; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D015507:Drugs, Investigational