Drug induced shortening of the QT/QTc interval: an emerging safety issue warranting further modelling and evaluation in drug research and development?
BACKGROUND
A session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh.


METHODS
The session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing "for" and "against" QT/QTc shortening being a safety issue and a panel discussion with the audience.


RESULTS
Compared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future.


CONCLUSIONS
Currently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.
Pfizer, Global Safety Pharmacology, Pfizer, PGRD, Sandwich, Kent, UK. mark.holbrook@pfizer.com
Mark
M
Holbrook
Marek
M
Malik
Rashmi R
RR
Shah
Jean-Pierre
JP
Valentin
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000175:diagnosis; D054316:Biomarkers, Pharmacological; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000639:trends; D064420:Drug-Related Side Effects and Adverse Reactions / Q000150:complications*; D004562:Electrocardiography / Q000187:drug effects / Q000706:statistics & numerical data; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000150:complications* / Q000517:prevention & control; D012606:Scotland
D054316:Biomarkers, Pharmacological