Comparison of QTc data analysis methods recommended by the ICH E14 guidance and
exposure-response analysis: case study of a thorough QT study of asenapine.
Author(s): Chapel S, Hutmacher MM, Bockbrader H, de Greef R, Lalonde RL.
Affiliation(s): Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann
Arbor, Michigan, USA. sunny.chapel@a2pg.com
Publication date & source: 2011, Clin Pharmacol Ther. , 89(1):75-80
An assessment of the effects of asenapine on QTc interval in patients with
schizophrenia revealed a discrepancy between the results obtained by two
different methods: an intersection-union test (IUT) (as recommended in the
International Conference on Harmonisation E14 guidance) and an exposure-response
(E-R) analysis. Simulations were performed in order to understand and reconcile
this discrepancy. Although estimates of the time-matched, placebo-corrected mean
change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R
analysis ranged from 2 to 5 ms per dose level, the IUT applied to simulated data
from the E-R model yielded maximum ddQTc estimates of 7-10 ms for the various
doses of asenapine. These results indicate that the IUT can produce biased
estimates that may induce a high false-positive rate in individual thorough QTc
trials. In such cases, simulations from an E-R model can aid in reconciling the
results from the two methods and may support the use of E-R results as a basis
for labeling.
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