Parviz Ghahramani (1), Tatiana Khariton (1), Timothy J Carrothers (1)
(1) Forest Research Institute, Jersey City, NJ, USA
Objectives: To compare two approaches for evaluating the relationship between drug concentrations and QTc interval.
Methods: Data from two dedicated thorough QT (TQT) studies were used to compare two common approaches [1,2] used in evaluating concentration-QTc relationships for both escitalopram (ESC, n=107 subjects) and citalopram (CIT, n=119 subjects). The first approach (delta-delta) specified baseline-and-placebo-adjusted QTc as the dependent variable and considered linear mixed-effects models based on observed drug plasma concentrations, with or without log-transformation. The second approach (covariate model) utilized nonlinear mixed-effects models with QTc as the dependent variable, and with terms for baseline, placebo effect, and drug effect (used an Emax model, with intersubject variability on baseline and Emax as a function of individual predicted concentrations). Comparison of the two approaches was made via simulation of the QTc change at steady state Cmax.
Results: For both studies, the delta-delta analysis approach yielded models with population median intercepts that excluded zero (e.g., -19.6 ms for CIT), which would be physiologically unlikely (i.e., indicate QTc shortening at low concentrations). For the CIT study, both approaches gave similar mean predictions of drug-related prolongation, but with different confidence intervals:
|
CIT Dose |
Mean QTc Prolongation (ms, 90% CI) |
|
|
Delta-delta |
Covariate model |
|
|
20 mg |
7.8 (6.2, 9.3) |
8.2 (6.5, 10.4) |
|
40 mg |
12.6 (10.9, 14.3) |
12.5 (10.1, 15.6) |
|
60 mg |
16.0 (14.0, 18.1) |
15.5 (12.2, 19.7) |
For the ESC study, the two approaches gave different predictions (mean and 90 CI) of drug-related QTc prolongation. At 20 mg dose, the delta-delta approach estimated a mean (90% CI) QTc change of 6.6 ms (5.3, 7.9), but the covariate approach estimated 8.3 ms (7.3, 9.2).
Conclusions: Modeling QTc directly using the covariate approach may provide a more physiologically relevant model for predictions across the full concentration range. On the other hand, the delta-delta approach may be computationally less intensive. While both approaches examined above avoid the multiple comparison bias and inefficiency of the Intersection Union Test commonly used in E14-standard TQT studies [3], they may provide different results. Additional validation work is recommended in comparing the relative merits of each C-QT approach.
References:
[1] Garnett CE et al. J Clin Pharm 2008;48:13-18.
[2] Piotrovsky V. AAPSJ 2005 ;7:E609-E624.
[3] Hutmacher MM et al. J Clin Pharm 2008;48:215-224.
Reference: PAGE 22 () Abstr 2994 [www.page-meeting.org/?abstract=2994]
Poster: Safety (e.g. QT prolongation)