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Virtual Thorough QT (TQT) Trial—Extrapolation of In Vitro Cardiac Safety Data to In Vivo Situation Using Multi-Scale Physiologically Based Ventricular Cell-wall Model Exemplified with Tolterodine and Fesoterodine

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...

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and...

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a ‘virtual twin’ of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram...

The Role of Interaction Model in Simulation of Drug Interactions and QT Prolongation

Computational modelling is a cornerstone of Comprehensive In Vitro Proarrhythmia Assay and is re-increasingly being used in drug development. Electrophysiological effects of drug-drug interactions can be predicted in silico, e.g. with the use of in vitro cardiac ion channel data, PK profiles and human ventricular cardiomyocyte models. There are, however, several approaches with...

Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations

Standards Conflict of Interest Sebastian Polak is an employee of Simcyp Ltd. (part of Certara). Human and Animal Rights and Informed Consent This article does not contain any studies with human animal

Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials

Background Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and...

Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence

Electrical phenomena located within the plasma membrane of the mammalian cardiac cells are connected with the cells’ main physiological functions—signals processing and contractility. They were extensively studied and described mathematically in so-called Hodgkin–Huxley paradigm. One of the physiological parameters, namely cell electric capacitance, has not been analyzed in-depth... a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition

Background Drugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate...

BDTcomparator: a program for comparing binary classifiers

BIOINFORMATICS APPLICATIONS NOTE Kamil Fijorek 1 Damian Fijorek Barbara Wisniowska 0 Sebastian Polak 0 Associate Editor: Jonathan Wren 0 Unit of Pharmacoepidemiology and Pharmacoeconomics

Age and gender dependent heart rate circadian model development and performance verification on the proarrhythmic drug case study

Background There are two main reasons for drug withdrawals at the various levels of the development path – hepatic and cardiac toxicity. The latter one is mainly connected with the proarrhythmic potency and according to the present practice is supposed to be recognized at the pre-clinical (in vitro and animal in vivo) or clinical level (human in vivo studies). There are, although...

Model of the Distribution of Diastolic Left Ventricular Posterior Wall Thickness in Healthy Adults and Its Impact on the Behavior of a String of Virtual Cardiomyocytes

project. Conflict of Interest Sebastian Polak is an employee of Simcyp (part of Certara) which develops computer platform specialized in the drugs cardiac safety assessment (Cardiac Safety Simulator). The