Pharmacogenetic issues in thorough QT trials.
Drug-induced QT prolongation (DI-LQT), through its associated arrhythmias, is a leading cause of drugs being withdrawn from the market. As a consequence, the US FDA and other regulatory agencies are mandating that all new drugs go through a so-called 'Thorough QT' (TQT) study to evaluate the potential for 'QT liability', specifically the potential for a drug to cause a discernible increase in the QT interval. Several genetic factors that modulate the risk of DI-LQT have been discovered. These are genes responsible for the congenital long QT syndrome, drug metabolism genes (mainly CYP2D6 and CYP3A4), and genes in other regulatory pathways. Here, we briefly review the links between genetic variants and drug-induced QT risk, and propose approaches to consider for using pharmacogenetics in planning and analyzing TQT studies.
Judson
Richard S
RS
SpyroPharma, Guilford, Connecticut, USA.
Salisbury
Benjamin A
BA
Reed
Carol R
CR
Ackerman
Michael J
MJ
D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D002986:Clinical Trials as Topic; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D010597:Pharmacogenetics; D016171:Torsades de Pointes / Q000139:chemically induced / Q000235:genetics
D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human