An Overview of QT Interval Assessment in Safety Pharmacology

Philippe Guillaume1, Sonia Goineau1, Guillaume Froget1

1 Porsolt SAS, Le Genest‐Saint‐Isle, France
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 10.7
DOI:  10.1002/0471141755.ph1007s61
Online Posting Date:  June, 2013
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Abstract

Medicinal products that prolong cardiac repolarization, as assessed in terms of prolongation of the QT interval of the electrocardiogram, may trigger torsade de pointe, a potentially fatal arrhythmia. The lethality of this risk necessitates a detailed preclinical evaluation before initiating clinical trials. The strategy for assessing the potential of new chemical entities to cause QT interval prolongation involves two complementary approaches. An in vivo test provides information on the potential of the agent to prolong the QT interval under near‐physiological conditions. The results are mostly descriptive, providing little insight into the mechanisms of action. In vitro experiments provide more mechanistic data, although the test procedure is far removed from the clinical situation. While both approaches have reasonable predictive value, the results may depend largely on the experimental conditions employed. Discussed in this unit are experimental issues that should be considered when testing agents for their potential to cause arrhythmias, as well as general strategies for understanding the problems associated with this cardiovascular risk. Curr. Protoc. Pharmacol. 61:10.7.1‐10.7.14 © 2013 by John Wiley & Sons, Inc.

Keywords: cardiac risk assessment; drug‐induced arrhythmias; QT interval prolongation; safety pharmacology; torsades de pointes

     
 
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Table of Contents

  • Introduction
  • Cardiac Arrhythmias and QT Interval Prolongation: A Clinical Background
  • Safety Pharmacology: Critical Parameters
  • Strategic Approach for Safety Pharmacology Studies
  • General Conclusions
  • LITERATURE CITED
  • Figures
  • Tables
     
 
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Materials

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Literature Cited

LITERATURE CITED
   Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunsky, M., and Romey, G. 1996. K(V)LQTS and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384:78‐80.
   Batey, A.J. and Doe, C.P. 2002. A method for QT correction based on beat‐to‐beat analysis of the QT/RR interval relationship in conscious telemetered beagle dogs. J. Pharmacol. Toxicol. Methods 48:11‐19.
   Bazett, H.C. 1920. An analysis of the time‐relations of electrocardiograms. Heart 7:353‐362.
   Carlsson, L., Amos, G.J., Andersson, B., Drews, L., Duker, G., and Wadstedt, G. 1997. Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: Implications for proarrhythmic potential? J. Pharm. Exp. Ther. 282:220‐227.
   Cavero, I., Mestre, M., Guillon, J.‐M., and Crumb, W. 2000. Drugs that prolong QT as unwanted effect: Assessing their likelihood of inducing hazardous cardiac dysrhythmias. Exp. Opin. Pharmacother. 2:947‐973.
   Colatsky, T.J. and Argentieri, T. 1994. Potassium channel blockers as antiarrhythmic drugs. Drug Dev. Res. 33:235‐249.
   Davis, A.S. 1998. The pre‐clinical assessment of QT interval prolongation: A comparison of in vitro and in vivo methods. Hum. Exp. Tox. 17:677‐680.
   Demolis, J.L., Charransol, A., Funck‐Brentano, C., and Jaillon, P. 1996. Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers. Br. J. Clin. Pharmacol. 41:499‐503.
   Drolet, B., Vincent, F., Rail, J., Chahine, M., Desche***nes, D., Nadeau, S., Khalifa, M. Hamelin, B.A., and Turgeaon, J. 1999. Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current. J. Pharmacol. Exp. Ther. 288:1261‐1268.
   Dumotier, B.M., Adamantidis, M.M., Puisieux, F.L., Bastide, M.M., and Dupuis, B.A. 1999. Repercussions of pharmacologic reduction in ionic currents on action potential configuration in rabbit fibers: Are they indicative of proarrhythmic potential? Drug Dev. Res. 47:63‐76.
   Eckardt, L., Haverkamp, W., Borggrefe, M., and Breithardt, G. 1998. Experimental models of torsade de pointes. Cardiovasc. Res. 39:178‐193.
   El Sherif, N., Bekheit, S.S., and Henkin, R. 1989. Quinidine‐induced long QTU interval and torsades de pointes: Role of bradycardia‐dependent early afterdepolarizations. J. Am. Cell. Cardiol. 14:252‐257.
   Ficker, E., Kuryshev, Y.A., Dennis, A.T., Obejero‐Paz, C., Wang, L., Hawryluk, P., Wible, B.A., and Brown, A.M. 2004. Mechanisms of arsenic‐induced prolongation of cardiac repolarization. Mol. Pharmacol. 66:33‐44.
   Fridericia, L.S. 1920. Die Systolendauer im Elektrocardiogramm bei Normalen Menschen und bei Herzkranken. Acta Med. Scand. 53:469‐486.
   Funk‐Brentano, C. and Jaillon, P. 1993. Rate‐corrected QT interval: Techniques and limitations. Am. J. Cardiol. 72:17B‐22B.
   Garnett, C.E., Zhu, H., Malik, M., Fossa, A.A., Zhang, J., Badilini, F., Li, J., Darpö, B., Sager, P., and Rodriguez, I. 2012. Methodologies to characterize the QT/corrected QT interval in the presence of drug‐induced heart rate changes or other autonomic effects. Am. Heart J. 163:912‐930.
   Goineau, S., Picard, S., and Lacroix, P. 2004. Species‐ and gender‐related effects of moxifloxacin on cardiac repolarization in isolated purkinje fibers. J. Pharmacol. Toxicol. Methods 49:217‐239.
   Goineau, S., Castagné, V., Guillaume, P., and Froget, G. 2012. The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine‐induced cardiac effects. J. Pharmacol. Toxicol. Methods 66:52‐58.
   Guth, B.D. 2007. Preclinical cardiovascular risk assessment in modern drug development. Toxicol. Sci. 97:4‐20.
   Guth, B.D., Gerrmeyer, S., Kolb, W., and Markert, M. 2004. Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization. J. Pharmacol. Toxicol. Methods 49:159‐169.
   Hamlin, R.L. 2007. The guinea pig in cardiac safety pharmacology. J. Pharmacol. Toxicol. Methods 55:1‐2.
   Hammond, T.G., Carlsson, L., Davis, A.S., Lynch, W.G., MacKenzie, I., Redfern, W.S., Sullivan, A.T., and Camm, A.J. 2001. Methods of collecting and evaluating non‐clinical cardiac electrophysiology data in the pharmaceutical industry: Results of an international survey. Cardiovasc. Res. 49:741‐750.
   Holzgrefe, H.H., Cavero, I., Gleason, C.R., Warner, W.A., Buchanan, L.V., Gill, M.W., Burkett, D.E., and Durham, S.K. 2007, Novel probabilistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys. J. Pharmacol. Toxicol. Methods 55:159‐175.
   ICH Harmonized Tripartite Guideline (S7A). 2000. Safety Pharmacology Studies for human Pharmaceuticals. Available from http://www.ich.org/products/guidelines/safety/article/safety‐guidelines.html.
   ICH Harmonized Tripartite Guideline (S7B). 2005. The Non‐Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. Available from http://www.ich.org/products/guidelines/safety/article/safety‐guidelines.html.
   Jackman, W.M., Friday, K.J., Anderson, J.L., Aliot, E.M., Blark, M., and Lezzara, R. 1988. The long QT syndromes: A critical review, new clinical observations and a unifying hypothesis. Prog. Cardiovasc. Dis. 31:115‐172.
   Jaillon, P., Dupuis, B., and Dahan, R. 1997. Études electrophysiologiques pre‐cliniques et cliniques en vue de la prediction d'un effet proarythmique (torsades de pointes) iatrogene. Therapie 52:271‐280.
   Kirsch, G.E., Trepakova, E.S., Brimecombe, J.C., Sidach, S.S., Erickson, H.D., Kochan, M.C., Shyjka, L.M., Lacerda, A.E., and Brown, A.M. 2004. Variability in the measurement of hERG potassium channel inhibition: Effects of temperature and stimulus pattern. J. Pharmacol. Toxicol. Methods. 50:93‐101.
   Kuryshev, Y.A., Ficker, E., Wang, L., Hawryluk, P., Dennis, A.T., Wible, B.A., Brown, A.M., Kang, J., Chen, X.L., Sawamura, K., Reynolds, W., and Rampe, D. 2005. Pentamidine‐induced long QT syndrome and block of hERG trafficking. J. Pharmacol. Exp. Ther. 312:316‐323.
   Lacroix, P. and Provost, D. 2000. Basic safety pharmacology: The cardiovascular system. Therapie 55:63‐69.
   Lee, N., Authier, S., Pugsley, M.K., and Curtis, M.J. 2010. The continuing evolution of torsades de pointes liability testing methods: Is there an end in sight? Toxicol. Appl. Pharmacol. 243:146‐153.
   Malik, M. 2001. Problems of heart rate correction in assessment of drug‐induced QT interval prolongation. J. Cardiovasc. Electrophysiol. 12:411‐420.
   Market, M., Klumpp, A., Trautman, T., Mayer, K., Stubhan, M., and Guth, B. 2007. The value added by measuring myocardial contractility “in vivo” in safety pharmacological profiling of drug candidates. J. Pharmacol. Toxicol. Methods 56:203‐211.
   Market, M., Shen, R., Trautman, T., and Guth, B. 2011. Heart rate correction models to detect QT interval prolongation in novel pharmaceutical development. J. Pharmacol. Toxicol. Methods 64:25‐41.
   Martin, R.L., McDermott, J.S, Salmen, H.J., Palmatier, J., Cox, B.F., and Gintant, G.A. 2004. The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: Influence of multi‐channel block. J. Cardiovasc. Pharmacol. 43:369‐379.
   Moore, E.N. 1993. Mechanisms and models to predict a QTc effect. Am. J. Cardiol. 72:4B‐9B.
   Morganroth, J. 1993. Relations of QTc prolongation on the electrocardiogram to torsades de pointes: Definitions and mechanisms. Am. J. Cardiol. 72:10B‐13B.
   Neyroud, N., Tesson, F., Denjoy, I., Leibovici, M., Donger, C., Barhanin, J., Faure, S., Gary, F., Coumel, P., Petit, C., Schwartz, K., and Guicheney, P. 1997. A novel mutation in the potassium channel gene KVLQT1 causes the Jerwell and Lange‐Nielsen cardioauditory syndrome. Nat. Genet. 15:186‐189.
   Olsson, B., Brorson, L., and Varnauskas, E. 1973. Class 3 antiarrhythmic action in man. Observations from monophasic action potential recordings and amiodarone treatment. Br. Heart J. 35:1255‐1259.
   Patterson, E., Scherlag, B.J., Szabo, B., and Lazzara, R. 1997. Facilitation of ephinephrine‐induced afterdepolarizations by class III antiarrhythmic drugs. J. Electrocardiol. 30:217‐224.
   Picard, S., Goineau, S., Guillaume, P., Henry, J., Hnaouz, J.L., and Rouet, R. 2011. Supplementary studies for cardiovascular assessment in safety pharmacology: A critical overview. Cardiovasc. Toxicol. 11:285‐307.
   Platia, E.V., Weisfeldt, M.L., and Franz, M.R. 1988. Immediate quantification of antiarrhythmic drug effect by monophasic action potential recording in coronary artery disease. Am. J. Cardiol. 61:1284‐1287.
   Porsolt, R.D. 1998. Safety pharmacology: A critical perspective. Drug Dev. Res. 41:51‐57.
   Pourrias, B., Porsolt, R.D., and Lacroix, P. 1999. QT interval prolongation by non‐cardiovascular drugs: A proposed assessment strategy. Drug Dev. Res. 47:55‐62.
   Priori, S.G., Mantica, M., and Schwartz, P.J. 1988. Delayed afterdepolarizations elicited in vivo by left stellate ganglion stimulation. Circulation 78:178‐185.
   Puisieux, F.L., Adamantidis, M.M., Dumotier, B.M., and Dupuis, B.A. 1996. Cisapride‐induced prolongation of cardiac action potential and early afterdepolarizations in rabbit Purkinje fibres. Br. J. Pharmacol. 117:1377‐1379.
   Rampe, D., Murawsky, M.K., Grau, J., and Lewis, E.W. 1998. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG1. J. Pharmacol. Exp. Ther. 286:788‐793.
   Redfern, W.S., Carlsson, L., Davis, A.S., Lynch, W., MacKenzie, I., Palethorpe, S., Siegl, P., Strang, I., Sullivan, A., and Wallis, R. 2003. Relationship between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32‐45.
   Sanguinetti, M.C., Jiang, C., Curran, M.E., and Keating, M.T. 1995. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299‐307.
   Stroobandt, R., Brachmann, J., Kesteloot, H., Kubler, W., and Senges, J. 1986. Effect of sotalol, aprindine and the combination aprindine‐sotalol on monophasic action potential duration. Eur. Heart J. 7:47‐53.
   Sullivan, A.T. and Kinter, L.B. 1995. Status of safety pharmacology in the pharmaceutical industry. Drug Dev. Res. 35:166‐172.
   Thomas, S.H. 1994. QT interval abnormalities and ventricular arrhythmias. Adverse Drug React. Toxicol. Rev. 13:77‐102.
   Van de Water, A., Verheyen, J., Xhonneux, R., and Reneman, R.S. 1989. An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J. Pharmacol. Methods 22:207‐217.
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