Application of cardiac electrophysiology simulations to pro‐arrhythmic safety testing

Abstract

Concerns over cardiac side effects are the largest single cause of compound attrition during pharmaceutical drug development. For a number of years, biophysically detailed mathematical models of cardiac electrical activity have been used to explore how a compound, interfering with specific ion-channel function, may explain effects at the cell-, tissue- and organ-scales. With the advent of high-throughput screening of multiple ion channels in the wet-lab, and improvements in computational modelling of their effects on cardiac cell activity, more reliable prediction of pro-arrhythmic risk is becoming possible at the earliest stages of drug development. In this paper, we review the current use of biophysically detailed mathematical models of cardiac myocyte electrical activity in drug safety testing, and suggest future directions to employ the full potential of this approach.LINKED ARTICLEThis article is commented on by Gintant, pp. 929–931 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02096.x

In silico assessment of drug safety in human heart applied to late sodium current blockers

“…Recently, however, advanced computational technology for in-silico assessment of the efficacy and safety of specific drugs has emerged as a complementary and potentially valuable tool. 28,29,60 Notable research efforts have been made to link molecular dynamics to biophysical models. 61 Other detailed models of drug/ ion-channel interaction take into account the rate of binding and unbinding 62 and can be reproduced in either Hodgkin-Huxley or Markov models formulations.…”

“…61 Other detailed models of drug/ ion-channel interaction take into account the rate of binding and unbinding 62 and can be reproduced in either Hodgkin-Huxley or Markov models formulations. 28,63,64 For example a recent study on the atrial-selectivity of ranolazine is based on a markovian model of its inhibiting effects on the sodium channels. 65,66 In the present study we have used a classical measure of the drug action, by employing IC 50 data, that is the fraction of block of the targeted channel conductance.…”

“…[22][23][24] Within the past 3 y, computer simulations have been employed in drug development programs with the goal of assessing in silico risk for drug-induced cardiac arrhythmia. [25][26][27][28] However, only Mirams et al 25 and Sarkar et al 29 utilized human AP models, in addition to models of the rabbit and dog ventricular APs.…”

Resolving the Three-Dimensional Histology of the Heart

“…Computational models have been proposed, and are increasingly being applied, as a way to link spatio-temporal scales, complementing traditional "wet-lab" approaches and projecting between bench and bed-side [15,16]. State-of-the-art models link protein structures of ion-channels to cell electrophysiology, multi-cellular coupling, and representations of heart anatomy that take into account locally prevailing cell alignment (usually, if inaccurately in terms of the histological substrate, termed fiber orientation), projecting through to clinical relevance, such as for drug actions [17,18,19].…”

The Cardiac Electrophysiology Web Lab

“…The need becomes particularly acute as models begin to be used in simulation studies for applications such as drug safety testing (7,(10)(11)(12) where we rely on behavioural predictions beyond the 'normal' regime in which many models were originally developed and tested.…”