Dataset Information

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

ABSTRACT:

Introduction

Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this.

Methods

We quantified the variability associated with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro™ screens when detecting block of I(Kr) (hERG), I(Na) (NaV1.5), I(CaL) (CaV1.2), I(Ks) (KCNQ1/minK) and I(to) (Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for I(CaL) (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations.

Results

There are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound's ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant.

Discussion

Our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound's action to acceptable levels, to allow a meaningful interpretation of the data.

SUBMITTER: Elkins RC

PROVIDER: S-EPMC4135079 | biostudies-literature | 2013 Jul-Aug

REPOSITORIES: biostudies-literature

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Publications

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

Elkins Ryan C RC Davies Mark R MR Brough Stephen J SJ Gavaghan David J DJ Cui Yi Y Abi-Gerges Najah N Mirams Gary R GR

Journal of pharmacological and toxicological methods 20130505 1

<h4>Introduction</h4>Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more ...[more]

PMID: 23651875

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Project description:IntroductionDrugs that prolong the QT interval on the electrocardiogram present a major safety concern for pharmaceutical companies and regulatory agencies. Despite a range of assays performed to assess compound effects on the QT interval, QT prolongation remains a major cause of attrition during compound development. In silico assays could alleviate such problems. In this study we evaluated an in silico method of predicting the results of a rabbit left-ventricular wedge assay.MethodsConcentration-effect data were acquired from either: the high-throughput IonWorks/FLIPR; the medium-throughput PatchXpress ion channel assays; or QSAR, a statistical IC50 value prediction model, for hERG, fast sodium, L-type calcium and KCNQ1/minK channels. Drug block of channels was incorporated into a mathematical differential equation model of rabbit ventricular myocyte electrophysiology through modification of the maximal conductance of each channel by a factor dependent on the IC50 value, Hill coefficient and concentration of each compound tested. Simulations were performed and agreement with experimental results, based upon input data from the different assays, was evaluated.ResultsThe assay was found to be 78% accurate, 72% sensitive and 81% specific when predicting QT prolongation (>10%) using PatchXpress assay data (77 compounds). Similar levels of predictivity were demonstrated using IonWorks/FLIPR data (121 compounds) with 78% accuracy, 73% sensitivity and 80% specificity. QT shortening (<-10%) was predicted with 77% accuracy, 33% sensitivity and 90% specificity using PatchXpress data and 71% accuracy, 42% sensitivity and 81% specificity using IonWorks/FLIPR data. Strong quantitative agreement between simulation and experimental results was also evident.DiscussionThe in silico action potential assay demonstrates good predictive ability, and is suitable for very high-throughput use in early drug development. Adoption of such an assay into cardiovascular safety assessment, integrating ion channel data from routine screens to infer results of animal-based tests, could provide a cost- and time-effective cardiac safety screen.

Dataset Information

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

Introduction

Methods

Results

Discussion

Publications

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

Similar Datasets

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