Abstract
QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs.
Highlights
Adverse effect of drugs on cardiac electrophysiology especially incidents of torsade de pointes (TdP) is one of the most prominent cause of withdrawal of several marketed drugs towards the end of the twentieth century and beginning of the 21st [1,2,3,4]
As TdP is a type of polymorphic ventricular tachycardia or arrhythmia, there is an association between prolongation of QT interval of electrocardiogram (ECG) and TdP
Tolterodine separated by extensive metaboliser (EM) (N = 27) and poor metaboliser (PM) (N = 21) groups, are reported along with clinical ΔΔQTcF data for 2- and 4-mg dose groups in Fig. 1a, b, respectively
Summary
Adverse effect of drugs on cardiac electrophysiology especially incidents of torsade de pointes (TdP) is one of the most prominent cause of withdrawal of several marketed drugs towards the end of the twentieth century and beginning of the 21st [1,2,3,4]. As TdP is a rare and multi-factorial event, it is very difficult to predict. Actual incidence of TdP can be a result of multiple clinical risk factors other than drug’s ability to perturb cardiac electrophysiology making it rare and challenging to predict its risk precisely. A drug that can prolong QT interval could potentially cause TdP. In 2006, the ICH issued a first formal guidance (E14) in this regard—BThe Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for NonAntiarrhythmic Drugs^ [8]. The major aspect of the guidance was the thorough QT/QTc (TQT) study that is a dedicated and well-controlled clinical
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