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

• Published in: The AAPS journal Vol. 20; no. 5; p. 83
• Main Authors: Patel, Nikunjkumar, Wisniowska, Barbara, Polak, Sebastian
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2018
• Subjects: Action Potentials - drug effects; Benzhydryl Compounds - pharmacokinetics; Benzhydryl Compounds - toxicity; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Biotransformation; Computer Simulation; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Dose-Response Relationship, Drug; Genotype; Heart Rate - drug effects; Heart Ventricles - drug effects; Heart Ventricles - physiopathology; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Models, Cardiovascular; Muscarinic Antagonists - pharmacokinetics; Muscarinic Antagonists - toxicity; Pharmacogenomic Variants; Pharmacology/Toxicology; Pharmacy; Phenotype; Research Article; Risk Assessment; Tolterodine Tartrate - pharmacokinetics; Tolterodine Tartrate - toxicity; Torsades de Pointes - chemically induced; Torsades de Pointes - physiopathology; hERG; tolterodine; arrhythmia; Cardiac Safety Simulator; fesoterodine; torsade de pointes; thorough QT trial; cardiac safety
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-018-0244-3

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 ( I Kr , I Na , I CaL ). 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.