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.
Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann Arbor, Michigan, USA. sunny.chapel@a2pg.com
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D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000453:epidemiology; D015982:Bias; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D003986:Dibenzocycloheptenes; D003987:Dibenzothiazepines / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005189:False Positive Reactions; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D008954:Models, Biological; D010601:Pharmacology, Clinical / Q000379:methods*; D017410:Practice Guidelines as Topic; D000069348:Quetiapine Fumarate; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D003987:Dibenzothiazepines; D006576:Heterocyclic Compounds, 4 or More Rings; D000069348:Quetiapine Fumarate; C522667:asenapine