Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.
OBJECTIVE
To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects.


METHODS
To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models.


RESULTS
This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)).


CONCLUSIONS
We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.
a Simcyp Limited (a Certara Company), Blades Enterprise Centre , Sheffield , UK.
Mitra
M
Abbasi
a Simcyp Limited (a Certara Company), Blades Enterprise Centre , Sheffield , UK.
Ben G
BG
Small
a Simcyp Limited (a Certara Company), Blades Enterprise Centre , Sheffield , UK.
Nikunjkumar
N
Patel
a Simcyp Limited (a Certara Company), Blades Enterprise Centre , Sheffield , UK.
Masoud
M
Jamei
a Simcyp Limited (a Certara Company), Blades Enterprise Centre , Sheffield , UK.|b Faculty of Pharmacy , Jagiellonian University Medical College , Krakow , Poland.
Sebastian
S
Polak
D000200:Action Potentials / Q000187:drug effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000009:adverse effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects*
D015507:Drugs, Investigational
In silico assessment; QT prolongation; cardiac arrhythmias; drug safety; early afterdepolarization; in silico screening