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

Journal of Pharmacological and Toxicological Methods

Volumn 68, Issue 1, 2013, Pages 112-122

  Elkins, Ryan C ^a   Davies, Mark R ^a   Brough, Stephen J ^b   Gavaghan, David J ^c   Cui, Yi ^b   Abi Gerges, Najah ^a   Mirams, Gary R ^c  

^a ASTRAZENECA   (United Kingdom)

^b GLAXOSMITHKLINE   (United Kingdom)

^c UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Action potential; Cardiac safety; Compound screening; High throughput; Mathematical model; Uncertainty; Variability

Indexed keywords

10,10 BIS(4 PYRIDINYLMETHYL) 9(10H) ANTHRACENONE; ALFUZOSIN; AMITRIPTYLINE; CALCIUM CHANNEL; CISAPRIDE; DILTIAZEM; DOFETILIDE; FLECAINIDE; HALOPERIDOL; HARKOSERIDE; ION CHANNEL; NICARDIPINE; NIFEDIPINE; NILOTINIB; PIMOZIDE; POTASSIUM CHANNEL HERG; POTASSIUM CHANNEL KCNE1; POTASSIUM CHANNEL KCNQ1; QUINIDINE; SODIUM CHANNEL NAV1.5; TETRACAINE; TOLTERODINE; VERAPAMIL;

ARTICLE; CARDIOTOXICITY; CELL FUNCTION; COMPUTER ANALYSIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG SAFETY; DRUG SCREENING; HIGH THROUGHPUT SCREENING; LABORATORY DEVICE; MEMBRANE POTENTIAL; PREDICTION; QUANTITATIVE ANALYSIS; SCREENING TEST; SIMULATION;

[FAST] TRANSIENT OUTWARD POTASSIUM CURRENT; ACTION POTENTIAL; ACTION POTENTIAL (DURATION); AP(D); ASTRAZENECA; AZ; CARDIAC SAFETY; COMPOUND SCREENING; CONCENTRATION FOR 50% INHIBITION; FAST SODIUM CURRENT; FLIPR; FLUOROMETRIC IMAGING PLATE READER; GLAXOSMITHKLINE; GSK; HIGH THROUGHPUT SCREENING [ASSAYS]; HIGH-THROUGHPUT; HTS; I(CAL); I(KR); I(KS); I(NA); I(TO); IC(50); L-TYPE CALCIUM CURRENT; MATHEMATICAL MODEL; MINUS LOG(10) OF IC(50); PDF; PIC(50); POPULATION PATCH CLAMPING; PPC; PROBABILITY DENSITY FUNCTION; QT(C); QTINTERVAL OF THE ELECTROCARDIOGRAM (CORRECTED FOR HEART RATE); RAPID DELAYED RECTIFIER POTASSIUM CURRENT; SLOW DELAYED RECTIFIER POTASSIUM CURRENT; TEN TUSSCHER AND PANFILOV (2006) HUMAN VENTRICULAR CELL MODEL; THOROUGH QT, HUMAN CLINICAL QT PROLONGATION TRIAL; TQT; TT06; UNCERTAINTY; VARIABILITY;

ACTION POTENTIALS; CELL LINE; COMPUTER SIMULATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; ION CHANNELS; MODELS, THEORETICAL; MYOCYTES, CARDIAC; PATCH-CLAMP TECHNIQUES; TOXICITY TESTS;

TETRA;

EID: 84880039259     PISSN: 10568719     EISSN: 1873488X     Source Type: Journal    
DOI: 10.1016/j.vascn.2013.04.007     Document Type: Article

References (37)

1. Beattie K.A., Luscombe C., Williams G., Munoz-Muriedas J., Gavaghan D.J., Cui Y., et al. Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. Journal of Pharmacological and Toxicological Methods 2013, 68(1):88-96. (this issue).
2. Bridgland-Taylor M., Hargreaves A., Easter A., Orme A., Henthorn D., Ding M., et al. Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks ht. Journal of Pharmacological and Toxicological Methods 2006, 54:189-199. 10.1016/j.vascn.2006.02.003.
3. Clayton R., Bernus O., Cherry E., Dierckx H., Fenton F., Mirabella L., et al. Models of cardiac tissue electrophysiology: Progress, challenges and open questions. Progress in Biophysics and Molecular Biology 2011, 104:22-48. 10.1016/j.pbiomolbio.2010.05.008.
4. Cooper J., Corrias A., Gavaghan D., Noble D. Considerations for the use of cellular electrophysiology models within cardiac tissue simulations. Progress in Biophysics and Molecular Biology 2011, 107:74-80. 10.1016/j.pbiomolbio.2011.06.002.
5. Cooper J., Mirams G., Niederer S. High-throughput functional curation of cellular electrophysiology models. Progress in Biophysics and Molecular Biology 2011, 107:11-20. 10.1016/j.pbiomolbio.2011.06.003.
6. Dale T.J., Townsend C., Hollands E.C., Trezise D.J. Population patch clamp electrophysiology: A breakthrough technology for ion channel screening. Molecular BioSystems 2007, 3:714-722. 10.1039/b706152h.
7. Dangerfield C., Kay D., Burrage K. Modeling ion channel dynamics through reflected stochastic differential equations. Physical Review E 2012, 85:051907.
8. Davies M., Mistry H., Hussein L., Pollard C., Valentin J.-P., Swinton J., et al. An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. American Journal of Physiology - Heart and Circulatory Physiology 2012, 302:H1466-H1480. 10.1152/ajpheart.00808.2011.
9. Finkel A., Wittel A., Yang N., Handran S., Hughes J., Costantin J. Population patch clamp improves data consistency and success rates in the measurement of ionic currents. Journal of Biomolecular Screening 2006, 11:488-496. 10.1177/1087057106288050.
10. Fletcher K., Shah R., Thomas A., Tobin F., Rodríguez B., Mirams G., et al. Novel approaches to assessing cardiac safety-proceedings of a workshop: Regulators, industry and academia discuss the future of in silico cardiac modelling to predict the proarrhythmic safety of drugs. Drug Safety 2011, 34:439-443. 10.2165/11591950-000000000-00000.
11. Gillie D.J., Novick S.J., Donovan B.T., Payne L.A., Townsend C. Development of a high-throughput electrophysiological assay for the human ether-à-go-go related potassium channel hERG. Journal of Pharmacological and Toxicological Methods 2013, 67:33-44. 10.1016/j.vascn.2012.10.002.
12. Gintant G. An evaluation of hERG current assay performance: Translating preclinical safety studies to clinical QT prolongation. Pharmacology and Therapeutics 2011, 129:109-119.
13. Golden A., Li N., Chen Q., Lee T., Nevill T., Cao X., et al. Ionflux: A microfluidic patch clamp system evaluated with human ether-a-go-go related gene channel physiology and pharmacology. Assay and Drug Development Technologies 2011, 9:608-619.
14. Harmer A., Abi-Gerges N., Easter A., Woods A., Lawrence C., Small B., et al. Optimisation and validation of a medium-throughput electrophysiology-based hnav1. 5 assay using IonWorks. Journal of Pharmacological and Toxicological Methods 2008, 57:30-41. 10.1016/j.vascn.2007.09.00.
15. Hill A.V. Proceedings supplement: The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. The Journal of Physiology 1910, 40:iv-vii.
16. Hindmarsh A., Brown P., Grant K., Lee S., Serban R., Shumaker D., et al. SUNDIALS: Suite of nonlinear and differential/algebraic equation solvers. ACM Transactions on Mathematical Software (TOMS) 2005, 31:363-396. 10.1145/1089014.1089020.
17. Hodgkin A., Huxley A. A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of Physiology 1952, 117:500-544.
18. Lloyd C., Lawson J., Hunter P., Nielsen P. The CellML model repository. Bioinformatics 2008, 24:2122-2123. 10.1093/bioinformatics/btn390.
19. Ly J., Shyy G., Misner D. Assessing hERG channel inhibition using PatchXpress. Clinics in Laboratory Medicine 2007, 27:201-208.
20. Mathes C., Friis S., Finley M., Liu Y. Qpatch: The missing link between HTS and ion channel drug discovery. Combinatorial Chemistry & High Throughput Screening 2009, 12:78-95.
21. Mirams G., Arthurs C., Bernabeu M., Bordas R., Cooper J., Corrias A., et al. Chaste: An open source C++ library for computational physiology and biology. PLoS Computational Biology 2013, 9:e1002970. 10.1371/journal.pcbi.100297.
22. Mirams G., Cui Y., Sher A., Fink M., Cooper J., Heath B., et al. Simulation of the multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk. Cardiovascular Research 2011, 91:53-61. 10.1093/cvr/CVR044.
23. Mirams G., Davies M., Cui Y., Kohl P., Noble D. Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing. British Journal of Pharmacology 2012, 197:932-945. 10.1111/j.1476-5381.2012.02020.x.
24. Mirams G., Noble D. Is it time for in silico simulation of drug cardiac side effects?. Annals of the New York Academy of Sciences 2011, 1245:44-47. 10.1111/j.1749-6632.2011.06324.x.
25. to) expression and regulation. Journal of Molecular and Cellular Cardiology 2010, 48:12-25.
26. Noble D. A modification of the Hodgkin-Huxley equations applicable to Purkinje fibre action and pacemaker potentials. The Journal of Physiology 1962, 160:317.
27. Noble D., Garny A., Noble P. How the Hodgkin-Huxley equations inspired the Cardiac Physiome project. The Journal of Physiology 2012, 590:2613-2628. 10.1113/jphysiol.2011.224238.
28. Pitt-Francis J., Pathmanathan P., Bernabeu M., Bordas R., Cooper J., Fletcher A., et al. Chaste: A test-driven approach to software development for biological modelling. Computer Physics Communications 2009, 180:2452-2471. 10.1016/j.cpc.2009.07.01.
29. Pollard C., Gerges N., Bridgland-Taylor M., Easter A., Hammond T., Valentin J. An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk. British Journal of Pharmacology 2010, 159:12-21.
30. Polonchuk L. Toward a new gold standard for early safety: Automated temperature-controlled hERG test on the PatchLiner. Frontiers in Pharmacology 2012, 3:3.
31. Roden D. Cellular basis of drug-induced Torsades de Pointes. British Journal of Pharmacology 2008, 154:1502-1507. 10.1038/bjp.2008.238.
32. Schroeder K., Neagle B. FLIPR: A new instrument for accurate, high throughput optical screening. Journal of Biomolecular Screening 1996, 1:75-80.
33. Schroeder K., Neagle B., Trezise D., Worley J. IonWorks™ ht: A new high-throughput electrophysiology measurement platform. Journal of Biomolecular Screening 2003, 8:50-64.
34. Stett A., Burkhardt C., Weber U., Van Stiphout P., Knott T. Cytocentering: A novel technique enabling automated cell-by-cell patch clamping with the cytopatch chip. Receptors & Channels 2003, 9:59-66.
35. Sullivan E., Tucker E., Dale I. Measurement of [ca2+] using the fluorometric imaging plate reader (FLIPR). Methods in molecular biology 1999, 114:125-133. Humana Press. 10.1385/1-59259-250-3:125. D. Lambert (Ed.).
36. Ten Tusscher K., Panfilov A. Alternans and spiral breakup in a human ventricular tissue model. American Journal of Physiology - Heart and Circulatory Physiology 2006, 291:1088-1100. 10.1152/ajpheart.00109.2006.
37. Wood C., Williams C., Waldron G. Patch clamping by numbers. Drug Discovery Today 2004, 9:434-441.