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Utility of concentration‐effect modeling and simulation in a thorough QT study of losmapimod
Author(s) -
Barbour April M.,
Magee Mindy,
Shaddinger Bonnie,
Arya Niki,
Tombs Lee,
Tao Wenli,
Patel Bela R.,
Fossler Michael J.,
Glaser Ruchira
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.465
Subject(s) - moxifloxacin , medicine , qt interval , placebo , dosing , confidence interval , statistical analysis , anesthesia , pharmacology , statistics , mathematics , chemistry , antibiotics , alternative medicine , pathology , biochemistry
A thorough QT study was conducted in healthy volunteers with losmapimod. Four treatment regimens were included: a therapeutic dose (7.5 mg BID for 5 days), a supratherapeutic dose (20 mg QD for 5 days), a positive control (400 mg moxifloxacin single dose on Day 5), and placebo for 5 days. Baseline and on treatment ECGs were measured on Day 1 (3 timepoints predose) and Day 5, respectively. The primary statistical analysis failed to demonstrate a lack of effect of losmapimod on the QT interval leading to a positive finding. However, simulations using the concentration‐effect model established for QTcF vs. losmapimod concentration at concentrations 4× the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90%CI (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and baseline differences between the treatments. Considering the results of the concentration‐effect modeling, previous losmapimod data, and the high false‐positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false‐positive.