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

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. Clinical Pharmacology & Therapeutics (2011) 89 1, 75–80. doi: 10.1038/clpt.2010.220