Exposure-response modeling approach for assessing QT effect in "thorough" QT/QTc studies.
We assess the QT effect using an exposure-response model in a "thorough QT/QTc study" with a four-period crossover design in which the treatments are placebo, positive control, higher dose of investigational drug, and therapeutic dose of investigational drug. In the study, QTc interval values and the drug concentrations are obtained for several specified times during treatment. This approach to the assessment of non-inferiority of the higher dose to placebo is an alternative strategy suggested in ICH-E14 guideline (Section 2.2.5) to the intersection-union test.
Hosmane
Balakrishna
B
Northern Illinois University, DeKalb, Illinois, USA. bala@math.niu.edu
Locke
Charles
C
Chiu
Yi-Lin
YL
D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000706:statistics & numerical data; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D015233:Models, Statistical; D009010:Monte Carlo Method; D015990:Placebo Effect; D013997:Time Factors