Monika Twarogowska (1), Géraldine Ayral (1), Pauline Traynard (1), Jonathan Chauvin (1)
(1) Lixoft, Antony, France
Introduction: Evaluation of cardiovascular safety is an important element of a new drug development. It aimes to detect a drug-induced delay in the ventricular repolarisation – a possible cause of fatal arrhythmia – measured by the prolongation of the QT interval. In 2015, the International Council for Harmonisation (ICH) E14 guidance agreed to use a model-based study of concentration-QT data as a primary analysis in the proarrhythmic risk assessment. Reproducible, quantitative methods are necessary for regulatory submissions. Currently recommended guidelines, on how to perform and report C-QTc analysis, follow the methodologies presented in the “Scientific white paper on concentration-QTc modelling” by Ch. Garnett et al. (2017) [1].
Objectives: The aim of this work is to present the implementation in MonolixSuite of the C-QTc analysis as recommended by the E14 guidelines and the white paper [1]. The study is based on the data of Dofetilide, which is a class III antiarrhythmic agent known to have a QT prolongation effect. Results show the C-QTc modelling workflow and simulations of the standard criteria for a drug-induced QTc interval prolongation.
Methods:
- The dataset [2] contains PK measurements and ECG recordings of 22 healthy subjects from a randomized, double-blind, 2-period crossover clinical trial, who received a single dose of 500mg of Dofetilide or placebo.
- Heart rate corrected QT (QTc) intervals were obtained with the Fridericia’s formula, which is currently the standard adopted by the FDA. Derived baseline-adjusted QTc interval (ΔQTc) and baseline-adjusted placebo-corrected QTc interval (ΔΔQTc) were used as model variables.
- The pre-specified linear mixed effect models, given in the FDA guidelines and in [1], depend on the concentration and include fixed effect parameters for: slope, intercept, influence of baseline on the intercept, treatment effects and effect of the nominal time after the first-dose. Subject-level random effects are added to the intercept and the slope.
- The models were implemented and their parameters were estimated in a straightforward way in Monolix.
- Simulx, a MonolixSuite application, was used to perform risk assessment simulations: two-sided 90% confidence interval for model derived baseline adjusted – placebo corrected QTc interval (ΔΔQTc).
Results: Monolix was used to fit the Dofetilide PK data with a two-compartments model with a time delay for the absorption and the baseline-adjusted QTc with the pre-specified linear mixed effect model. A joint modelling approach, where both QTc and PK models parameters are estimated simultaneously, was compared with the FDA recommended approach, where the C-QTc model uses directly the observed time-matched PK data. Both methods yielded very close estimates. The estimated parameters and their standard errors were used to calculate the estimated mean QTc change from baseline and the 90% confidence interval for a large range of Cmax concentrations. For Cmax concentrations above 0.5 ng/mL, the estimated mean QTc change from the baseline exceeded the 10 ms safety threshold. The advantage of the joint PK-QTc model is that the QT interval prolongation can be studied for different doses and designs (instead of different Cmax values). For instance, in case of a 125 mg q12h regimen, 88% of patients had the QT prolongation longer than 10 ms.
Conclusions: The presented work shows step-by-step how the FDA recommended workflow for C-QTc analysis can be implemented in Monolix. The procedure is generic and can be applied to other compounds in the same way.
References:
[1] Garnett C., Bonate P. L., Dang Q., Ferber G., Huang D., and Liu J.; Scientific white paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018 Jun; 45(3):383-397
[2] Johannesen L., Vicente J., Mason J.W., Sanabria C., Waite-Labott K., Hong M., Guo P., Lin J., Sørensen J.S., Galeotti L., Florian J., Ugander M., Stockbridge N., Strauss D.G.; Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil. Clin Pharmacol Ther. 2014 Nov; 96(5):549-58
Reference: PAGE () Abstr 9390 [www.page-meeting.org/?abstract=9390]
Poster: Drug/Disease Modelling - Safety