ToxComp ∔ In vitro-in vivo extrapolation system for drug proarrhythmic potency assessment

The project aims to develop the systems biology driven, modeling and simulation based, easy to use for non-modelers platform for the drugs proarrhythmic potency assessment at the population level. Platform realizes the in vitro-in vivo extrapolation approach thus the input data comes from the patch clamp in vitro ionic currents inhibition studies. Covariates describing variability in population include cardiomyocyte, heart and plasma physiological parameters which are correlated with basic demographic information (age, gender). Simulated output data includes action potential and ECG derivatives where APD50, APD90 and QTc are analyzed as the endpoints. System was implemented with use of the Java/JavaFX technology and is available both on line and off line and distributed under the GPLv3 license. Its main role include clinical trials optimization and waiving, helping with the go-no go decision making.

[1]  D Noble,et al.  A meta‐analysis of cardiac electrophysiology computational models , 2009, Experimental physiology.

[2]  A. Sjögren,et al.  Left ventricular wall thickness determined by ultrasound in 100 subjects without heart disease. , 1971, Chest.

[3]  Sebastian Polak,et al.  Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence , 2012, Journal of Cardiovascular Translational Research.

[4]  D. Noble,et al.  A model for human ventricular tissue. , 2004, American journal of physiology. Heart and circulatory physiology.

[5]  S. Polak,et al.  hERG in vitro interchange factors—development and verification , 2009, Toxicology mechanisms and methods.

[6]  S. Polak,et al.  Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment , 2012, Toxicology mechanisms and methods.

[7]  Jeffrey M. Hausdorff,et al.  Physionet: Components of a New Research Resource for Complex Physiologic Signals". Circu-lation Vol , 2000 .

[8]  A. Rostami-Hodjegan,et al.  Physiologically Based Pharmacokinetics Joined With In Vitro–In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology , 2012, Clinical pharmacology and therapeutics.

[9]  Sjögren Al,et al.  Left Ventricular Wall Thickness Determined by Ultrasound in 100 Subjects without Heart Disease , 1971 .

[10]  Hugh A. Barton,et al.  Database for Physiologically Based Pharmacokinetic (PBPK) Modeling: Physiological Data for Healthy and Health-Impaired Elderly , 2009, Journal of toxicology and environmental health. Part B, Critical reviews.