Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods

AbstractModeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C- ∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound , AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile mixed models (LQMM) implemented via LQMM package; (ii) different model structures with and without tre atment- or time-specific intercepts; and (iii) three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations). We show that treatment- and time-specific intercepts may need to be included into C-∆ QTc modeling through PROC MIXED or LME4, regardless of their statistical significance. With the intersection union test (IUT) in the TQT study as a reference for comparison, inclusion of these intercepts increased the feasibility for C-∆QTc modelling of SAD or MAD to reach the same conclusion as t he IUT analysis based on TQT study. Compared to PROC MIXED or LME4, the LQMM method is less dependent on inclusion of treatment- or time-specific intercepts, and the ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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