ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation.
BACKGROUND
Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause TdP and prolong QT interval in humans.


METHODS
Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs.


RESULTS
The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe.


CONCLUSIONS
Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety.
Hanson
Laurie A
LA
Worldwide Safety Sciences, Pfizer Inc., 7000 Portage Road, Kalamazoo, MI 49001, USA.
Bass
Alan S
AS
Gintant
Gary
G
Mittelstadt
Scott
S
Rampe
David
D
Thomas
Karluss
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D009412:Nerve Fibers / Q000502:physiology; D018408:Patch-Clamp Techniques; D010599:Pharmacokinetics; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D013686:Telemetry; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human