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Authors Grenier J, Paglialunga S, Morimoto BH, Lester RM
Received 2 October 2017
Accepted for publication 23 February 2018
Published 18 April 2018 Volume 2018:10 Pages 27—36
DOI https://doi.org/10.2147/DHPS.S133286
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Professor Rajender Aparasu
Abstract: The assessment of a drug’s cardiac liability has undergone
considerable metamorphosis by regulators since International Council for
Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14
guideline was introduced in 2005. Drug developers now have a choice in how
proarrhythmia risk can be evaluated; the options include a dedicated thorough
QT (TQT) study or exposure response (ER) modeling of intensive
electrocardiogram (ECG) captured in early clinical development. The alternative
approach of ER modeling was incorporated into a guidance document in 2015 as a
primary analysis tool which could be utilized in early phase dose escalation
studies as an option to perform a dedicated TQT trial. This review will
describe the current state of ER modeling of intensive ECG data collected
during early clinical drug development; the requirements with regard to the use
of a positive control; and address the challenges and opportunities of this
alternative approach to assessing QT liability.
Keywords: concentration-effect
modeling, thorough QT study, intensive ECG collection, intersection union test,
QT/QTc, assay sensitivity, positive control, moxifloxacin