Novel Approaches to Assessing Cardiac Safety – Proceedings of a Workshop

Fletcher, Katherine; Shah, Rajiv; Thomas, Arthur W.; Tobin, Frank; Rodríguez, Blanca; Mirams, Gary R.; Sáiz, Javier; Noble, Denis

doi:10.2165/11591950-000000000-00000

Cited by 19 publications

(10 citation statements)

References 1 publication

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“…Given that by the use of current AP assays (1,26), the number of compounds that can be assessed early in discovery is very limited. Application of a computational approach at a stage in the drug discovery phase where there are many compounds to choose from may not only reduce the demand for carrying out the primary cell AP assays (e.g., this is consistent with our commitment for replacing, reducing, and refining animal testing) but also allow for more cost-and resource-efficient design of compounds with improved safety profile (13,16). In a recent article Rodriguez et al (45) suggested the potential need to prepare/rebuild models for the assessment of pharmacological safety.…”

Section: Discussionmentioning

confidence: 89%

“…Since the description of the first ventricular cardiac model (5), multiple models have been published to represent different aspects of the electrophysiology of ventricular myocytes, including how drug interactions with ICs alter the electrophysiological behavior of these cells (8,14). Application of novel in silico approaches to assessing cardiac safety has recently received significant attention (16,45). In a recent article Mirams et al (36) show that simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.…”

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confidence: 99%

“…Positive controls hIERG Cisapride was solubilized in DMSO at a concentration of 3 mM and further diluted in PBS to make a top test concentration of 10 M. hINa and hIto Flecainide was solubilized in DMSO at a concentration of 95 mM and further diluted in PBS to make a top test concentration of 31.6 M. hIKs XE991 was solubilized in DMSO at a concentration of 9.5 mM and further diluted in PBS to make a top test concentration of 31.6 M. hICa Verapamil was solubilized in DMSO at a concentration of 316 mM and further diluted in HPBS ϩ Ba 2ϩ to make a top test concentration of 100 M. them are activators), 12, 20, and 19 (4 of them are activators) compounds selected for this investigation show activity (IC 50 value Ͻ30 M) against hKv11.1, hKv7.1/hminK, hKv4.3/hKChIP2.2, hNav1.5, and hCav1.2, respectively. Additionally,16 out of these 53 compounds were found to be selective inhibitors and active against only one IC and 12 of the panel were found to have activity against more than four ICs. Reference compounds and chemicals were purchased from Apin Chemicals (Oxon, UK), Calbiochem (Darmstadt, Germany), Tocris Bioscience (Bristol, UK), and Sigma-Aldrich Company (Poole, UK).…”

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confidence: 99%

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An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment

Davies

Mistry

Hussein

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 μM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

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Section: Discussionmentioning

confidence: 89%

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confidence: 99%

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confidence: 99%

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An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment

Davies

Mistry

Hussein

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…145 Related to this is the need for better access to, and consistency of, experimental data and meta-data. Specifically needed are: (i) good-quality data, including raw, rather than pre-analysed data sets, to allow later extraction of additional parameters; (ii) data from studies that suggest a lack of effect, to allow testing model specificity (‘negative’ data are useful); and (iii) standardized reporting guidelines, as experimental methods vary greatly between (and even within) laboratories, and will change over time as new technologies become available (an example of such a guideline is the recently proposed Minimum Information for Cardiac Electrophysiology Experiments , MICEE).…”

Section: Discussionmentioning

confidence: 99%

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Quinn

Kohl

2013

Cardiovascular Research

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Since the development of the first mathematical cardiac cell model 50 years ago, computational modelling has become an increasingly powerful tool for the analysis of data and for the integration of information related to complex cardiac behaviour. Current models build on decades of iteration between experiment and theory, representing a collective understanding of cardiac function. All models, whether computational, experimental, or conceptual, are simplified representations of reality and, like tools in a toolbox, suitable for specific applications. Their range of applicability can be explored (and expanded) by iterative combination of ‘wet’ and ‘dry’ investigation, where experimental or clinical data are used to first build and then validate computational models (allowing integration of previous findings, quantitative assessment of conceptual models, and projection across relevant spatial and temporal scales), while computational simulations are utilized for plausibility assessment, hypotheses-generation, and prediction (thereby defining further experimental research targets). When implemented effectively, this combined wet/dry research approach can support the development of a more complete and cohesive understanding of integrated biological function. This review illustrates the utility of such an approach, based on recent examples of multi-scale studies of cardiac structure and mechano-electric function.

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“…It has been suggested that multiple-ion-channel effects should be considered to provide a more accurate assessment of pro-arrhythmic risk ( Kramer et al, 2013; Mirams et al, 2011 ), and that simulations based on mathematical models for the electrophysiology of cardiac myocytes could be used to integrate information on how a compound affects different ion channels ( Fletcher et al, 2011; Gintant, 2012; Mirams, Davies, Cui, Kohl, & Noble, 2012; Mirams & Noble, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Prediction of Thorough QT study results using action potential simulations based on ion channel screens

Mirams

Davies²,

Brough

et al. 2014

Journal of Pharmacological and Toxicological Methods

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107

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IntroductionDetection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development.MethodsIon current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms — IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration–effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration.Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1 Hz and running to steady state, for a range of concentrations.ResultsWe compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥ 5 ms was predicted with up to 79% sensitivity and 100% specificity.DiscussionThis study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety assessment.

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Novel Approaches to Assessing Cardiac Safety – Proceedings of a Workshop

Cited by 19 publications

References 1 publication

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Prediction of Thorough QT study results using action potential simulations based on ion channel screens

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