Meta-Analysis of Moxifloxacin Concentration-QTc Effects with Application to Assay Sensitivity Assessment
Abstract
Abstract The International Council for Harmonization E14 guidance, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, recommends a thorough QT study as part of clinical drug development to investigate the potential of therapeutic drugs to delay cardiac repolarization. Moxifloxacin is often used as the positive control to demonstrate that the assay is sensitive in detecting QT effects. We performed a meta-analysis of moxifloxacin data to characterize the exposure-response relationship and determine the range of parameters related to assay sensitivity for moxifloxacin. The data are from 67 thorough QT studies submitted to FDA. We applied meta-analysis methods to evaluate the exposure-response relationship and estimated the parameters of two concentration-QTc models. We analyzed individual and pooled studies and demonstrated the homogeneity and heterogeneity of the moxifloxacin concentration-QTc relationships among the studies. We determined the reference range of study parameters that demonstrate assay sensitivity. The estimated slopes for individual studies ranged from 2.6 to 7.6 milliseconds per μ g/mL (95% tolerance interval for 90% of slope was 2.8 to 6.8 milliseconds per μ g/mL). The estimated treatment specific intercept for individual studies ranged from –2.1 to 7.3 milliseconds (95% tolerance interval for 90% of treatment specific intercept was –0.8 to 5.0 milliseconds).
How strong is the evidence?
Evidence Hub reads this as a meta-analysis. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
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