Pharmacogenetic issues in thorough QT trials

被引:7
作者
Judson, Richard S.
Salisbury, Benjamin A.
Reed, Carol R.
Ackerman, Michael J.
机构
[1] SpyroPharma, Guilford, CT USA
[2] Clin Data Inc, New Haven, CT USA
[3] Mayo Clin, Coll Med, Sudden Death Genom Lab, Rochester, MN USA
关键词
D O I
10.1007/BF03256454
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Drug-induced QT prolongation (DI-LQT), through its associated arrhythmias, is a leading cause of drugs being withdrawn from the market.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.
引用
收藏
页码:153 / 162
页数:10
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共 76 条
[51]  
Rashba EJ, 1998, CIRCULATION, V97, P451
[52]   Taking the "idio" out of "idiosyncratic": Predicting torsades de pointes [J].
Roden, DM .
PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY, 1998, 21 (05) :1029-1034
[53]   INCIDENCE AND CLINICAL-FEATURES OF THE QUINIDINE-ASSOCIATED LONG QT SYNDROME - IMPLICATIONS FOR PATIENT-CARE [J].
RODEN, DM ;
WOOSLEY, RL ;
PRIMM, RK .
AMERICAN HEART JOURNAL, 1986, 111 (06) :1088-1093
[54]   Drug therapy: Drug-induced prolongation of the QT interval [J].
Roden, DM .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (10) :1013-1022
[55]   Drug-induced QT prolongation in women during the menstrual cycle [J].
Rodriguez, I ;
Kilborn, MJ ;
Liu, XK ;
Pezzullo, JC ;
Woosley, RL .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2001, 285 (10) :1322-1326
[56]   Concomitant use of antipsychotics and drugs that may prolong the QT interval [J].
Roe, CM ;
Odell, KW ;
Henderson, RR .
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 2003, 23 (02) :197-200
[57]   Interaction with GM130 during HERG ion channel trafficking - Disruption by type 2 congenital long QT syndrome mutations [J].
Roti, ECR ;
Myers, CD ;
Ayers, RA ;
Boatman, DE ;
Delfosse, SA ;
Chan, EKL ;
Ackerman, MJ ;
January, CT ;
Robertson, GA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (49) :47779-47785
[58]  
SALISBURY BA, 2006, HEART RHYTHM, V3, pS98, DOI DOI 10.1016/J.HRTHM.2006.02.297
[59]   Molecular determinants of KCNQ1 channel block by a benzodiazepine [J].
Seebohm, G ;
Chen, J ;
Strutz, N ;
Culberson, C ;
Lerche, C ;
Sanguinetti, MC .
MOLECULAR PHARMACOLOGY, 2003, 64 (01) :70-77
[60]   A common polymorphism associated with antibiotic-induced cardiac arrhythmia [J].
Sesti, F ;
Abbott, GW ;
Wei, J ;
Murray, KT ;
Saksena, S ;
Schwartz, PJ ;
Priori, SG ;
Roden, DM ;
George, AL ;
Goldstein, SAN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (19) :10613-10618