Baseline selection in concentration-QTc modeling: impact on assay sensitivity.

ABSTRACT

The baseline selection in concentration-QTc (C-QTc) modeling is not well studied in the literature. Time-matched baseline and pre-dose baseline have been commonly used as a covariate in C-QTc modeling for parallel and crossover study, respectively. It has been showed that the C-QTc model using time-matched baseline has a low chance of showing assay sensitivity in parallel study. To better understand the impacts of baseline section in C-QTc, we examined the original and subsampled moxifloxacin and placebo data from more than 50 of TQT studies submitted to FDA with regard to assay sensitivity. Our analyses show that baseline selection (time-matched, pre-dose, average) has an impact on prediction from C-QTc modeling and the impact depends on study design (parallel, crossover). The impact to categorical table of ΔQTc is unlikely to alter the interpretation of the outlier category (ΔQTc>60) that corresponds to the regulatory concern. The results presented here can guide C-QTc study design as well as baseline selection in C-QTc modeling.