Delayed Effects in the Exposure-Response Analysis of Clinical QTc Trials

In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientif...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biopharmaceutical statistics 2012-03, Vol.22 (2), p.387-400
Main Authors: Glomb, Patricia, Ring, Arne
Format: Article
Language:English
Subjects:
Algorithms
Clinical trials
Clinical Trials as Topic - statistics & numerical data
Computer Simulation - statistics & numerical data
Data Interpretation, Statistical
Delay
Dose-Response Relationship, Drug
Drugs
Drugs, Investigational - adverse effects
Drugs, Investigational - analysis
Electrocardiography - drug effects
Estimation bias
Exposure
Exposure-response analysis
Foods
Heart Rate - drug effects
Humans
Hysteresis
ICH E14
International Cooperation
Intervals
Kinetics
Lag time
Linear Models
Long QT Syndrome - complications
Long QT Syndrome - drug therapy
Pharmacology
QTc prolongation
Recognition
Simulation
Statistics
Time Factors
Torsades de Pointes - etiology
United States
United States Food and Drug Administration
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.
ISSN:1054-3406
1520-5711
DOI:10.1080/10543406.2010.539309