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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: 2011-01, Clin Pharmacol Ther., 89(1):75-80. Epub 2010 Nov 24.

Publication type: Comparative Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

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.

Page last updated: 2011-12-09

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