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
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Comparative Study
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Antipsychotic Agents / administration & dosage
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Antipsychotic Agents / adverse effects*
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Antipsychotic Agents / blood
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Arrhythmias, Cardiac / chemically induced*
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Arrhythmias, Cardiac / epidemiology
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Bias
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Computer Simulation
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Data Interpretation, Statistical*
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Dibenzocycloheptenes
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Dibenzothiazepines / blood
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Dibenzothiazepines / therapeutic use
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Dibenzothiazepines / toxicity
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Dose-Response Relationship, Drug
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False Positive Reactions
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Heterocyclic Compounds, 4 or More Rings / administration & dosage
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Heterocyclic Compounds, 4 or More Rings / adverse effects*
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Heterocyclic Compounds, 4 or More Rings / blood
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Humans
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Models, Biological
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Pharmacology, Clinical / methods*
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Practice Guidelines as Topic
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Quetiapine Fumarate
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Schizophrenia / blood
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Schizophrenia / drug therapy*
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Toxicity Tests / methods*
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Toxicity Tests / standards
Substances
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Antipsychotic Agents
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Dibenzocycloheptenes
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Dibenzothiazepines
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Heterocyclic Compounds, 4 or More Rings
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Quetiapine Fumarate
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asenapine