Assessing proarrhythmic potential of drugs when optimal studies are infeasible.
Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed.
Rock
Edwin P
EP
GlaxoSmithKline R&D, King of Prussia, PA 19406-0930, USA. edwin.p.rock@gsk.com
Finkle
John
J
Fingert
Howard J
HJ
Booth
Brian P
BP
Garnett
Christine E
CE
Grant
Stephen
S
Justice
Robert L
RL
Kovacs
Richard J
RJ
Kowey
Peter R
PR
Rodriguez
Ignacio
I
Sanhai
Wendy R
WR
Strnadova
Colette
C
Targum
Shari L
SL
Tsong
Yi
Y
Uhl
Kathleen
K
Stockbridge
Norman
N
D000818:Animals; D018849:Controlled Clinical Trials as Topic / Q000379:methods; D017277:Drug Approval / Q000458:organization & administration; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015507:Drugs, Investigational / Q000009:adverse effects*; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D007391:International Cooperation; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology
D015507:Drugs, Investigational