title: Utility of concentration-effect modeling and simulation in a thorough QT study of losmapimod.
abstract: 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.
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: April M
authors.initials: AM
authors.lastname: Barbour
authors.forename: Mindy
authors.initials: M
authors.lastname: Magee
authors.forename: Bonnie
authors.initials: B
authors.lastname: Shaddinger
authors.forename: Niki
authors.initials: N
authors.lastname: Arya
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
authors.forename: Wenli
authors.initials: W
authors.lastname: Tao
authors.forename: Bela R
authors.initials: BR
authors.lastname: Patel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fossler
authors.forename: Ruchira
authors.initials: R
authors.lastname: Glaser
mesh_terms: D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage; D055815:Young Adult
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D024841:Fluoroquinolones; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D000077266:Moxifloxacin
keywords: QT; concentration-effect; losmapimod; modeling and simulation