title: Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials.
abstract: OBJECTIVE
  The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation.
  
  
  METHODS
  Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation.
  
  
  RESULTS
  The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval.
  
  
  CONCLUSIONS
  It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers.
authors: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1-2 Iron Bridge Road, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK. shuying.y.yang@gsk.com
authors: Shuying
authors: S
authors: Yang
authors: Misba
authors: M
authors: Beerahee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D003521:Cyclopropanes / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines