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Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials.
MedLine Citation:
PMID:  23325437     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: 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:
Shuying Yang; Misba Beerahee
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-17
Journal Detail:
Title:  European journal of clinical pharmacology     Volume:  -     ISSN:  1432-1041     ISO Abbreviation:  Eur. J. Clin. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1256165     Medline TA:  Eur J Clin Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1-2 Iron Bridge Road, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK, shuying.y.yang@gsk.com.
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