Pharmacokinetic and Pharmacodynamic Characterization of Non-antiarrhythmic QT-Prolonging Drugs Associated with Torsades
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Pharmacokinetic and Pharmacodynamic Characterization of Non-antiarrhythmic QT-Prolonging Drugs Associated With Torsades de Pointes QT-pdorging dncgs arc occasi@ associated with T d t s dc Pointts (Tdp). In this
were not greater those of nontorsadogms. The
i n m e s in AUC, dimination half-lives, vds t d ~we carpand thc p h m n B c ' d umes of distribution, b i d a b i l i t y and propit-dmuctaistics of QT-protein binding w- cxnnjmde between the two gtacps. Almost id torsadogms uaused an inlmy& m ' d d rHh TdP and tkost . . in- G ~ Q S Gin QT W a d gnats than 10 msec. In notasd&$MT&. lltechm&m&s d u d c d t k c a q y m a ~ e $ w ~ - EonfiQptr ~ ~ ~ only one nontorsadogm did. With ingdnrg* *tkcdruyeindnrgexpoaxomitant administmtion of enzyme inhibitm, torsadogaEFcaused an increase in QT i n t d mnging between 30 msec and 82 tmd pmtein binding; the in~eirrpTintavslcausedby the inaaasG m i 'QT intends in tkc thrarg CYP 3A4 done mc not l n & b O k i W h . n l e m s a t s ~ e d ' llccGlroarEly mac HMJ? to be p#vadyhic. t m d induced by thc '
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Yeong-liong lin, MD Center for Drug Evaluation. Taiwan
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Keith Cbon, PhD
Research Center for Drug Discovery, National YangMing University, Taiwan
Key Words Pharmacokinetic; Pharmacodynamic; QT prolongation; Torsades de Poinles
Correspondence Address Yeong-Liang Lin. MD, 1 E No. 15-1. Section I . Hangiou S Road, Taipei, Taiwan 100 (ernail: [email protected]).
INTRODUCTION Drug-associated cardiac arrhythmia and prolongation of QT intervals are issues of concern in the development, approval, and clinical use of new drugs. To address this concern, many guidelines have been developed to evaluate the risk of arrhythmia during drug development (1-4). Many factors have been recognized to increase the risk of Torsades de Pointes (TdP), for example, concomitant administration of medications known to prolong QT interval or of a QT-prolonging medication with a drug inhibiting its metabolism, as well as using QT-prolonging drugs in patients with electrolyte imbalances, congestive heart failure, and genetic predisposition to QT prolongation (3-6). Whether the increased risk can be translated
into pharmacologic characterization deserves investigation. In this study, we examined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of QT-prolonging drugs with a focus on properties that were closely related to drug interaction and therefore significantly affected the risk of TdF! We hypothesized that the characteristics of drugs associated with TdP may be different from those of drugs not associated with TdF! By comparing PK and PD characteristics of TdP versus non-TdP drugs, we hoped to find out whether certain patterns existed between the two categories of QT-prolonging drugs.
MATERIALS A N D METHODS To collect QT-prolonging drugs, we systemically reviewed the approval information of non-
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