PMID- 29181850
DCOM- 20180815
LR  - 20181113
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
VI  - 175
IP  - 4
DP  - 2018 Feb
TI  - Can non-clinical repolarization assays predict the results of clinical thorough
      QT studies? Results from a research consortium.
PG  - 606-617
LID - 10.1111/bph.14101 [doi]
AB  - BACKGROUND AND PURPOSE: Translation of non-clinical markers of delayed
      ventricular repolarization to clinical prolongation of the QT interval corrected 
      for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains 
      an issue in drug discovery and regulatory evaluations. We retrospectively
      analysed 150 drug applications in a US Food and Drug Administration database to
      determine the utility of established non-clinical in vitro IKr current human
      ether-a-go-go-related gene (hERG), action potential duration (APD) and in vivo
      (QTc) repolarization assays to detect and predict clinical QTc prolongation.
      EXPERIMENTAL APPROACH: The predictive performance of three non-clinical assays
      was compared with clinical thorough QT study outcomes based on free clinical
      plasma drug concentrations using sensitivity and specificity, receiver operating 
      characteristic (ROC) curves, positive (PPVs) and negative predictive values
      (NPVs) and likelihood ratios (LRs). KEY RESULTS: Non-clinical assays demonstrated
      robust specificity (high true negative rate) but poor sensitivity (low true
      positive rate) for clinical QTc prolongation at low-intermediate (1x-30x)
      clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs
      (ability to predict clinical QTc prolongation). ROC curves (overall test
      accuracy) and LRs (ability to influence post-test probabilities) demonstrated
      overall marginal performance for hERG and QTc assays (best at 30x exposures),
      while the APD assay demonstrated minimal value. CONCLUSIONS AND IMPLICATIONS: The
      predictive value of hERG, APD and QTc assays varies, with drug concentrations
      strongly affecting translational performance. While useful in guiding preclinical
      candidates without clinical QT prolongation, hERG and QTc repolarization assays
      provide greater value compared with the APD assay.
CI  - (c) 2017 The Authors. British Journal of Pharmacology published by John Wiley &
      Sons Ltd on behalf of British Pharmacological Society.
FAU - Park, Eunjung
AU  - Park E
AD  - Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
FAU - Gintant, Gary A
AU  - Gintant GA
AD  - Department of Integrative Pharmacology, AbbVie, North Chicago, IL, USA.
FAU - Bi, Daoqin
AU  - Bi D
AD  - Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
FAU - Kozeli, Devi
AU  - Kozeli D
AD  - Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
FAU - Pettit, Syril D
AU  - Pettit SD
AD  - HESI, Washington, DC, USA.
FAU - Pierson, Jennifer B
AU  - Pierson JB
AUID- ORCID: 0000-0002-9551-0681
AD  - HESI, Washington, DC, USA.
FAU - Skinner, Matthew
AU  - Skinner M
AD  - Drug Safety and Metabolism, AstraZeneca, Macclesfield, Cheshire, UK.
FAU - Willard, James
AU  - Willard J
AD  - Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
FAU - Wisialowski, Todd
AU  - Wisialowski T
AD  - Drug Safety Research and Development, Pfizer, Groton, CT, USA.
FAU - Koerner, John
AU  - Koerner J
AD  - Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
FAU - Valentin, Jean-Pierre
AU  - Valentin JP
AD  - Non-Clinical Development, UCB-Biopharma SPRL, Braine-l'Alleud, Belgium.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180115
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Cardiovascular Agents)
RN  - 0 (Drugs, Investigational)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
SB  - IM
MH  - Action Potentials/drug effects/physiology
MH  - Cardiovascular Agents/*pharmacology/therapeutic use
MH  - Drug Evaluation, Preclinical/methods
MH  - Drugs, Investigational/*pharmacology/therapeutic use
MH  - Ether-A-Go-Go Potassium Channels/agonists/antagonists & inhibitors/*physiology
MH  - Heart Rate/*drug effects/physiology
MH  - Humans
MH  - Long QT Syndrome/drug therapy/physiopathology
MH  - Retrospective Studies
MH  - Torsades de Pointes/drug therapy/physiopathology
PMC - PMC5786459
EDAT- 2017/11/29 06:00
MHDA- 2018/08/16 06:00
CRDT- 2017/11/29 06:00
PHST- 2016/08/25 00:00 [received]
PHST- 2017/10/12 00:00 [revised]
PHST- 2017/11/13 00:00 [accepted]
PHST- 2017/11/29 06:00 [pubmed]
PHST- 2018/08/16 06:00 [medline]
PHST- 2017/11/29 06:00 [entrez]
AID - 10.1111/bph.14101 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2018 Feb;175(4):606-617. doi: 10.1111/bph.14101. Epub 2018 Jan