The prospective IQ-CSRC trial: A prototype early clinical proarrhythmia assessment investigation for replacing the ICH E14 thorough QTc (TQT) study

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• 作者：Icilio Cavero^a ; ^{iciliocavero@outlook.com" class="auth_mail" title="E-mail the corresponding author} ; Henry Holzgrefe^b ; Mike Clements^c
• 关键词：AP ; cardiac action potential ; CiPA ; comprehensive in vitro proarrhythmia assay ; CSRC ; Cardiac Safety Research Consortium ; Cmax ; maximal plasma concentration ; CTWG ; clinical translational working group ; DRest ; rate-normalized Tpeak  ; &minus ;   ; Tend  ; =  ; Tpe interval ; ECG ; electrocardiogram ; E-R ; exposure-response ; FDA ; Food and Drug Administration ; FIH ; first-in-humans ; hERG ; human ether-à ; -go-go-related gene ; hiPSC-CMs ; human induced pluripotent stem cell derived cardiomyocyte
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：July-August 2016
• 年：2016
• 卷：80
• 期：Complete
• 页码：1-8
• 全文大小：428 K

文摘

Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA).

Topics

The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine.

Discussion

The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs.