Session S23.3

Systems Biology in Safety Assessment: Use of a Recalibrated Hund-Rudy Model to Predict the Effect of Novel Drug Compounds on Action Potential Duration

MR Davies*, H Mistry, N Abi-Gerges, C Pollard, J Swinton

AstraZeneca
Macclesfield, UK

Drug-induced ion channel modulation in ventricular myocytes can prolong action potential duration, which is seen on the electrocardiogram (ECG) as a prolongation of the QT interval. This is associated with a cardiac arrhythmia and therefore QT interval duration is carefully monitored in animal and man. Therefore, all candidate drugs are screened in an in vivo model of QT duration. This is however a late-stage and low throughput assay. For this reason, and much earlier in the drug discovery path, AstraZeneca screens compounds using IonWorks technology for their effects in vitro on the key cardiac ion channels. This information by itself is insufficient to infer APD change however.
We have taken a publicly available model of cardiac action potentials (Hund Rudy) and calibrated it against a series of DMSO-control experiments from a voltage-sensitive dye based assays on isolated canine ventricular myocytes (VM). This calibration allows us to capture the variation in inter- and intra-experimental drift and create an ensemble of parameter sets, differing only in the ion-channel densities, consistent with variations observed in electrophysiology experiments. We have then simulated the anticipated change in APD for a series of compounds with known channel inhibition profiles and compared this to experimentally derived estimates in order to assess the predictivity of the model.
Using a mathematical model of cardiac action potentials, we are able to integrate potency estimates from a range of ion channels and assess the potential QT risk that a particular compound may pose. This risk assessment can be performed at a much earlier stage in the drug pipeline and with the intention of improving drug decision making.

(Abstract Control Number: 90)