Simulation of Biological Processes phần 10 potx

and provide insight where these 10 models ¢t into the US Food & Drug

Administration (FDA) process required to develop a drug.

There are many examples that testify to the value of modelling in the discovery

and development process. One area of interest is in preventing unnecessary deaths

from cardiac arrhythmias. Though there are many di¡erent applications of models

in cardiovascular safety, a case study that we often point to is that of the

antiarrhythmic d-sotalol, which blocks the rapid component of the delayed

recti¢er current (IKr). Tested in 1996 via the SWORD (survivability with oral

d-sotalol) trial (Pratt et al 1998), d-sotalol was administered prophylactically to

patients surviving myocardial infarctions in the hope that it would reduce their

mortality from subsequent arrhythmic episodes. Unfortunately, mortality

increased with d-sotalol administration vs. placebo, and surprisingly, women

were found to be at much greater risk of death than men. The unanswered

question was why?

We constructed a series of canine ventricular myocyte models corresponding to

the three di¡erent cell types across the ventricular wall (epicardial, endocardial and

M cell), and incorporated modi¢cations accounting for data showing ventricular

myocytes from female rabbits having 15% less IKr density and 13% less IK1 density

compared to those from male rabbits. With no drug onboard, the simulated M cell

action potential from the female was only slightly di¡erent from that of the male.

As drug concentration is increased both male and female action potentials prolong,

however only a 50% blockage in IKr is required to begin to observe early after

depolarizations (EADs) in the female action potential, while 80% IKr block is

required to see the same e¡ect in male cells (Fig. 3). This result indicates a

threefold di¡erential in the male/female susceptibility to this drug. The reduction

in repolarizing currents expressed in females thus makes them more sensitive to

action potential abnormalities induced by IKr block. Though no speci¢c type of

arrhythmia was cited in the SWORD trial as leading to mortality, EADs are

commonly viewed as a marker for arrhythmic susceptibility. Therefore, our

modelling results suggested a possible cause for the gender di¡erence in mortality.

I want now to turn to the issue of integrating data to investigate the signi¢cance

of individual components in a complex system. The following will illustrate how

modelling can make logical inferences from available data to make testable

predictions. These predictions provide evidence as to the underlying

mechanisms, which is particularly useful when the underlying mechanisms

cannot be addressed by current experimental techniques.

Case example: indirect signalling in cardiac excitability

I previously mentioned that leveraging prior e¡orts is one of the powerful aspects

of our approach to modelling. Having discussed two separate Physiome

228 LEVIN ET AL

technologies representing two distinct scienti¢c areas, signal transduction and

electrophysiology, I want to present a case example that brings together these

two diverse areas. This example demonstrates Physiome Sciences’ ability to

integrate models from both a biological perspective as well as a software

implementation perspective. We have joined together two very distinct areas of

experimental research using our technology platform to couple separate models

into a single simulation of second messenger control of ion channel current. This

work was performed by a team of scientists at Physiome, in addition to the authors,

including Dr Adam Muzikant, Director of the Modeling Sciences Group, and Ms

Neelofur Wasti, in the same group, who provides data and literature support and

curation.

Drugs indirectly a¡ect the heart

In the case of d-sotalol, the compound was in fact an antiarrhythmic targeted

directly at the IKr channel to prolong the action potential. A more di⁄cult

problem to analyse is that of drugs that a¡ect ion channels of the heart despite

IN SILICO DRUG DEVELOPMENT 229

FIG. 3. Simulation of male and female canine M cell action potentials in the presence of a drug

that blocks the IKr channel. As drug concentration increases (top to bottom), an early after

depolarization (EAD) occurs at a lower drug concentration for the female than for the male

cell, which is indicated by the small heart symbol above the ¢rst EAD for each gender. These

EADs are thought to be a trigger for drug-induced arrhythmia. The basic cycle length (interval

between pacing stimuli) was 2500 ms.