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Reference: Mirams, GR, Cui, Y, Sher, A et al., (2011). Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk. Cardiovascular research, 91 (1), 53-61.Citable link to this page:

 

Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.

Abstract: AIMS: The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk. METHODS AND RESULTS: We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers. CONCLUSION: The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.

Publication status:Published

Bibliographic Details

Journal: Cardiovascular researchsee more from them

Issue Date: 2011-7

pages:53-61Identifiers

Urn: uuid:f7c85a24-cb5a-496e-9dc4-717c1a9d93f3

Source identifier: 237657

Eissn: 1755-3245

Doi: https://doi.org/10.1093/cvr/cvr044

Issn: 0008-6363 Item Description

Type: Journal article;

Language: eng Keywords: Animals Dogs Rabbits Humans Guinea Pigs Torsades de Pointes Calcium Channel Blockers Sodium Channel Blockers Ion Channels Calcium Channels, L-Type Sodium Channels Patch-Clamp Techniques Risk Assessment Transfection Dose-Response Relationship, Drug Action Potentials Kinetics Computer Simulation Ether-A-Go-Go Potassium Channels Models, Cardiovascular HEK293 Cells Risk Factors Potassium Channel Blockers NAV1.5 Voltage-Gated Sodium Channel Tiny URL: pubs:237657

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Author: Mirams, GR - - - Cui, Y - - - Sher, A - - - Fink, M - - - Cooper, J - - - Heath, BM - - - McMahon, NC - - - Gavaghan, DJ - instit

Source: https://ora.ox.ac.uk/objects/uuid:f7c85a24-cb5a-496e-9dc4-717c1a9d93f3



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