The effects of six antipsychotic agents on QTc—An attempt to mimic clinical trial through simulation including variability in the population
Section snippets
Background
The QT interval – the time between the start of the Q wave and the end of the T wave in the ECG – represents the measure of ventricular depolarization and repolarization. The QT interval prolongation is considered to be a biomarker for proarrhythmic risk, especially for a life-threatening arrhythmia—Torsades de Pointes (TdP) [1].
It has been found that many drugs belonging to different chemical and therapeutic groups, such as antiarrhythmics, antihistamines, antifungals, antipsychotics or
Methods
The Cardiac Safety Simulator (CSS) is a tool for in vitro–in vivo extrapolation of the cardiac effects of drugs (occurrence or absence of the QT interval prolongation in the simulated ECG trace and its scale). The experiment described in the current publication is based on data obtained from the literature-derived in vitro studies results (heterologously transfected HEK and CHO cells, and guinea pig VM) as presented in Table 1. Such drug-specific data, together with individual drugs
Results
Using the Cardiac Safety Simulator, six simulations for antipsychotic agents such as Haloperidol, Ziprasidone, Quetiapine, Olanzapine, Risperidone, Thioridazine were performed. The aim of the study was to evaluate the possibility of mimicking the results of the clinical trial through simulation.
Fig. 1 presents mean values of QTc prolongation after drug administration with their 95% confidence intervals. The simulated values were lower than those observed in the clinical trial for Haloperidol,
Discussion
In an attempt to repeat in silico the results of the clinical trial of six antipsychotic agents and their effects on QTc, six simulations were performed using the Cardiac Safety Simulator. For Olanzapine, Risperidone, Thioridazine simulated mean delta QTc values were greater than average values observed clinically, respectively by 0.9, 1.1 and 4.7 ms. For Haloperidol, Ziprasidone and Quetiapine, however, the results are undervalued respectively by 1.0, 14.4 and 1.6 ms, yet those differences are
Conclusions
To conclude, through computational simulations the average values of QTc prolongation were reproduced with acceptable accuracy of 5 in 6 agents; however, it failed to fully reproduce the variability in the studied populations. The problem of variability in the population that may affect the QT interval requires further study.
Background
The QT interval corresponds to ventricular depolarization and repolarization in the ECG. It is believed that excessive QT interval prolongation increases the risk of life-threatening ventricular arrhythmias. In order to reduce the likelihood of adverse drug reactions, the ICH E14 guidance recommends conducting a “thorough QT/QTc study” that aims to assess whether the drug has an effect on QT. Due to the fact that agents blocking ionic channels in the cell membrane of cardiomyocytes may
Conflict of interest statement
A.G. states no conflict of interest. S.P. is an employee of Simcyp Limited (part of Certara) which develops software for the cardiac safety assessment (Cardiac Safety Simulator).
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