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

Clin Pharmacol Ther. 2011 Jan;89(1):75-80. doi: 10.1038/clpt.2010.220. Epub 2010 Nov 24.

Abstract

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / blood
  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / epidemiology
  • Bias
  • Computer Simulation
  • Data Interpretation, Statistical*
  • Dibenzothiazepines / blood
  • Dibenzothiazepines / therapeutic use
  • Dibenzothiazepines / toxicity
  • Dose-Response Relationship, Drug
  • False Positive Reactions
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings / adverse effects*
  • Heterocyclic Compounds, 4 or More Rings / blood
  • Humans
  • Models, Biological
  • Pharmacology, Clinical / methods*
  • Practice Guidelines as Topic
  • Quetiapine Fumarate
  • Schizophrenia / blood
  • Schizophrenia / drug therapy*
  • Toxicity Tests / methods*
  • Toxicity Tests / standards

Substances

  • Antipsychotic Agents
  • Dibenzothiazepines
  • Heterocyclic Compounds, 4 or More Rings
  • Quetiapine Fumarate
  • asenapine