Models for profiling the potential QT prolongation risk of drugs.
The appearance of QT prolongation and arrhythmic events associated with a compound undergoing clinical trials can greatly hamper drug development programs. Assessing the risk of a compound during preclinical studies to cause this cardiotoxicity is thus critically important to the pharmaceutical industry. A wide variety of preclinical approaches exist to evaluate potential QT issues, including in vitro, in vivo and in silico (i.e., computer simulation) methods. We present an evaluation of recent reports implementing these techniques, with an emphasis on the linkage between drug-induced cardiac action potential changes and QT prolongation both in vitro and in silico. We conclude with a strategy that integrates in silico modeling with in vitro and in vivo experimentation to create a compelling package for assessing potential proarrhythmic risk of a compound.
Muzikant
Adam L
AL
Physiome Sciences Inc, 150 College Road West, Suite 300, Princeton, NJ 08540, USA. alm@physiome.com
Penland
R Christian
RC
D000818:Animals; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008954:Models, Biological