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3 - Cardiac safety

from I - SPECIFIC AREAS OF PREDICTIVE TOXICOLOGY

Published online by Cambridge University Press:  06 December 2010

By
Martin Traebert  and
Berengere Dumotier
Edited by
Jinghai J. Xu  and
Laszlo Urban
Jinghai J. Xu
Affiliation:
Merck Research Laboratory, New Jersey
Laszlo Urban
Affiliation:
Novartis Institutes for Biomedical Research, Massachusetts
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Summary

INTRODUCTION: THE STATUS OF THE PROBLEM

Over the last two decades, several medicines were withdrawn from the market because their use in patients has been discovered to be associated with the development of a very specific potentially life-threatening polymorphic ventricular tachycardia, Torsade de pointes (TdP). In approximately 20 percent of the cases, TdP can develop into ventricular fibrillation and lead to sudden death. The recently finalized ICH S7B guideline defines the prolongation of the QT interval (measure of time between Q and T waves in the electrocardiogram) on the surface electrocardiogram as an appropriate biomarker for predicting the torsadogenic risk of a given compound. However, a growing body of evidence suggests that the QT interval prolongation is an incomplete biomarker of a drug's torsadogenic potential. The generation of TdP is triggered more by dynamic combination of multiple predisposing factors and components and favored by myocardial substrate rather than by a single electrophysiological event. Following recommendations of the respective guideline, the pharmaceutical industry has intensively implemented methodologies to assess the potential risk of QT prolongation and TdP in man. The key task of each cardiac safety testing strategy requires a case-by-case analysis; how to find the best combination of different test capabilities considering their strengths and limitations to detect the liability of a chemical structure to induce lethal arrhythmia of very low clinical incidence. This chapter will provide a brief overview on the current methodologies and considerations that are useful in predicting QT prolongation in man and/or a torsadogenic liability.

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Predictive Toxicology in Drug Safety , pp. 34 - 53
Publisher: Cambridge University Press
Print publication year: 2010

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References

Cahoon, WD, Jr. Acquired QT prolongation. Prog Cardiovasc Nurs. 2009;24(1): 30–33.CrossRefGoogle ScholarPubMed
Sager, PT. Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug-induced torsades de pointes. Br J Pharmacol. 2008;154(7):1544–1549.CrossRefGoogle ScholarPubMed
Bode, G, Olejniczak, K.ICH topic: The draft ICH S7B step 2: Note for guidance on safety pharmacology studies for human pharmaceuticals. Fundam Clin Pharmacol. (2002);16(2):79–81.Google ScholarPubMed
,Committee for Proprietary Medicinal Product. Points to Consider. The Assessment of QT Interval Prolongation by Non-Cardiovascular Medicinal Products; 1997. CPMP/986/96.
,ICH Harmonized Tripartite Guideline. S7A Safety Pharmacology Studies for Human Pharmaceuticals. U.S. Department of Health and Human Services, FDA; 2000. Retrieved from http://www.ich.org.Google Scholar
,ICH S7B. The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. U.S. Department of Health and Human Services, FDA; 2005. Retrieved from http://www.ich.org.Google Scholar
Lagrutta, AA, Trepakova, ES, Salata, JJ. The hERG channel and risk of drug-acquired arrhythmia: An overview. Current Top Med Chem. 2008;8(13):1102–1112.CrossRefGoogle ScholarPubMed
Sanguinetti, MC, Jurkiewicz, NK. Two components of cardiac delayed rectifier K+ ­current. Differential sensitivity to block by class III antiarrhythmic agents. J. Gen Physiol. 1990;96:195–215.CrossRefGoogle ScholarPubMed
Sanguinetti, MC, Jiang, C, Curran, ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81,299−307.CrossRefGoogle ScholarPubMed
Sanchez-Chapula, JA, Navarro-Polanco, RA, Culberson, C, et al. Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. J Biol Chem. 2002;277(26):23587–23595.CrossRefGoogle ScholarPubMed
Kang, J, Chen, XL, Wang, L, et al. Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG. J Pharmacol Ex The. 2001;299(1):290–296.Google ScholarPubMed
Wang, Q, Curran, ME, Splawski, I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12(1):17–23.CrossRefGoogle ScholarPubMed
Crump, W, Cavero, I. QT interval prolongation by non-cardiovascular drugs: Issues and solutions for novel drug development. Pharm Sci Tech Today. 1999;2:270–280.CrossRefGoogle Scholar
DiFrancesco, D, Borer, JS. The funny current: Cellular basis for the control of heart rate. Drugs. 2007;67(15):15–24.CrossRefGoogle ScholarPubMed
Antzelevitch, C, Shimizu, W, Yan, GX, et al. The M cell: Its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol. 1999;10:1124–1152.CrossRefGoogle Scholar
Bassani, RA. Transient outward potassium current and Ca2+ homeostasis in the heart: Beyond the action potential. Braz J Med Biol Res. 2006;39(3):393–403.CrossRefGoogle ScholarPubMed
Antzelevitch, C. Role of spatial dispersion of repolarization in ­inherited and acquired ­sudden cardiac death syndromes. Am J Physiol Heart Circ Physiol. 2007;293(4):H2024–2038.CrossRefGoogle ScholarPubMed
Zhu, TG, Patel, C, Martin, S, et al. Ventricular transmural repolarization sequence: its relationship with ventricular relaxation and role in ventricular diastolic function. Eur Heart J. 2009;30(3):372–380.CrossRefGoogle ScholarPubMed
Taggart, P, Sutton, PMI, Opthof, T, et al. Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res. 2001;50:454–462.CrossRefGoogle ScholarPubMed
Drouin, E, Charpentier, F, Gauthier, C, et al. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. JACC. 1995;26(1):185–192.CrossRefGoogle ScholarPubMed
Antzelevitch, C. Drug-induced spatial dispersion of repolarization. Cardiol J. 2008;15(2):100–121.Google ScholarPubMed
Thai, KM, Ecker, GF. Predictive models for HERG channel blockers: Ligand-based and structure-based approaches. Curr Med Chem. 2007;14(28):3003–3026.CrossRefGoogle ScholarPubMed
Wempe, MF. Quaternary ammonium ions can externally block voltage-gated K+ channels. Establishing a theortical and experimental model that predicts KDs and the selectivity of K+ over Na+ ions. J Mol Struct. 2001;562:63–78.CrossRefGoogle Scholar
Ekins, S, Crumb, WJ, Sarazan, RD, et al. Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. J Pharmacol Exp Ther. 2002;301:427–434.CrossRefGoogle ScholarPubMed
Cavalli, A, Poluzzi, E, Ponti, F, et al. Toward a pharmacophore for drugs inducing the long QT syndrome: Insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002;45:3844–3853.CrossRefGoogle Scholar
Roche, O, Trube, G, Zuegge, J, et al. A virtual screening method for prediction of the HERG potassium channel liability of compound libraries. Chembiochem. 2002;3:455–459.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
Pearlstein, R, Vaz, RJ, Kanga, J, et al. Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches. Bioorg Med Chem Lett. 2003;3:1829–1835.CrossRefGoogle Scholar
Ermondi, G, Visentin, S, Caron, G. GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: The case of hERG K+ channel blockers. Eur J Med Chem. 2009;44:1926–1932.CrossRefGoogle ScholarPubMed
Sanguinetti, MC, Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature. 2002;23(440):463–469.Google Scholar
Roden, DM . Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10),1013−1022.CrossRefGoogle ScholarPubMed
Kirsch, GE, Trepakova, ES, Brimecombe, JC, et al. Variability in the measurement of hERG potassium channel inhibition: Effects of temperature and stimulus pattern. J Pharmacol Toxicol Methods. 2004;50(2):93−101.CrossRefGoogle ScholarPubMed
Stork, D, Timin, EN, Berjukow, S, et al. State dependent dissociation of HERG channel inhibitors. Br J Pharmacol. 2007;151(8):1368−1376.CrossRefGoogle ScholarPubMed
Redfern, WS, Carlsson, L, Davis, AS, et al. Relationships 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. 2003;58,32–45.CrossRefGoogle ScholarPubMed
Dennis, A, Wang, L, Wan, X, et al. hERG channel trafficking: Novel targets in drug-induced long QT syndrome. Biochem Soc Trans. 2007;35(5):1060–1063.CrossRefGoogle ScholarPubMed
Ficker, E, Kuryshev, YA, Dennis, AT et al. Mechanisms of arsenic-induced prolongation of cardiac repolarization. Mol Pharmacol. 2004;66(1):33–44.CrossRefGoogle ScholarPubMed
Kuryshew, YA, Ficker, E, Wang, L, et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther. 2005;312(1):316–323.CrossRefGoogle Scholar
Yuill, KH, Borg, JJ, Ridley, JM, et al. Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation. Biochem Biophys Res Commun. 2004;318(2):556–561.CrossRefGoogle ScholarPubMed
Dumotier, B, Bastide, M, Adamantidis, M. Use-dependent effects of cisapride on postrest action potentials in rabbit ventricular myocardium. Eur J Pharmacol. 2001;422(1–3):137–148.CrossRefGoogle ScholarPubMed
Puisieux, F, Adamantidis, M, Dumotier, B, et al. Cisapride-induced prolongation of cardiac action potential and early after depolarizations in rabbit Purkinje fibres. Br J Pharmacol. 1996;117,1377–1379.CrossRefGoogle ScholarPubMed
Franz, MR. Method and theory of monophasic action potential recording. Prog Cardiovasc Dis. 1991;6:347–368.CrossRefGoogle Scholar
Gintant, GA, Limberis, JT, McDermott, JS, et al. The canine Purkinje fiber: An in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol. 2001;37:607–618.CrossRefGoogle Scholar
Cavero, I, Mestre, M, Guillon, JM, et al. Preclinical in vitro cardiac electrophysiology: A method of predicting arrhythmogenic potential of antihistamines in humans?Drug Saf. 1991;21(Suppl 1):19–31.CrossRefGoogle Scholar
Li, H, Zhang, Y, Tian, Z, et al. Genistein stimulates myocardial contractility in guinea pigs by different subcellular mechanisms. Eur J Pharmacol. 2008;597(1–3): 70–74.CrossRefGoogle ScholarPubMed
Johna, R, Mertens, H, Haverkamp, W, et al. Clofilium in the isolated perfused rabbit heart: A new model to study proarrhythmia induced by class III antiarrhythmic drugs. Basic Res Cardiol. 1998;93(2):127–135.CrossRefGoogle ScholarPubMed
Hondeghem, LM, Hoffman, P. Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: Importance of triangulation reverse-use dependence and instability. J Cardiovasc Pharmacol. 2003;41:14−24.CrossRefGoogle ScholarPubMed
Brimecombe, JC, Kirsch, GE, Brown, AM. Test article concentrations in the hERG assay: Losses through the perfusion, solubility and stability. J Pharmacol Toxicol Methods. 2009;59(1):29–34.CrossRefGoogle ScholarPubMed
Fossa, AA. Assessing QT prolongation in conscious dogs: validation of a beat-to-beat method. Pharmacol Ther. 2008;119(2):133–140.CrossRefGoogle ScholarPubMed
Gauvin, DV, Tilley, LP, Smith, FW, Jr, et al. Electrocardiogram, hemodynamics, and core body temperatures of the normal freely moving cynomolgus monkey by remote radiotelemetry. J Pharmacol Toxicol Methods. 2006;53(2):140–151.CrossRefGoogle ScholarPubMed
Gralinski, MR. The dog's role in the preclinical assessment of QT interval prolongation. Toxicol Pathol. 2003;31:11–16.Google ScholarPubMed
Gauvin, DV, Tilley, LP, Smith, FW, Jr, et al. Electrocardiogram, hemodynamics, and core body temperatures of the normal freely moving laboratory beagle dog by remote radiotelemetry. J Pharmacol Toxicol Methods. 2006;53(2):128–139.CrossRefGoogle ScholarPubMed
Soloviev, MV, Hamlin, RL, Barrett, RM, et al. Different species require different correction factors for the QT interval. Cardiovasc Toxicol. 2006;6(2):145–157.CrossRefGoogle ScholarPubMed
Takahara, A, Sugiyama, A, Satoh, Y, et al. Comparison of four rate-correction algorithms for the ventricular repolarization period in assessing net effects of IKr blockers in dogs. J Pharmacol Sci. 2006;102(4):396–404.CrossRefGoogle ScholarPubMed
King, A, Bailie, M, Olivier, NB. Magnitude of error introduced by application of heart rate correction formulas to the canine QT interval. Ann Noninvasive Electrocardiol. 2006;11(4):289–298.CrossRefGoogle ScholarPubMed
Holzgrefe, HH, Cavero, I, Gleason, CR, et al. Novel probabilistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys. J Pharmacol Toxicol Methods. 2007;55(2):159–175.CrossRefGoogle ScholarPubMed
Webster, R, Leishmann, D, Walker, D. Towards a drug concentration effect relationship for QT prolongation and torsades des pointes. Curr Opin Drug Discov Devel. 2002;5:116–126.Google Scholar
Hondeghem, LM. QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart Rhythm. 2008;5(8):1210–1212.CrossRefGoogle ScholarPubMed
Gintant, GA. Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk. Pharmacol Ther. 2008; 119(2):199–209.CrossRefGoogle ScholarPubMed
Bass, AS, Darpo, B, Valentin, JP, et al. Moving towards better predictors of drug-induced torsades de pointes. Br J Pharmacol. 2008;154(7):1550–1553.CrossRefGoogle ScholarPubMed
Whitebread, S, Hamon, J, Bojanic, D, et al. Keynote review: In vitro safety pharmacology profiling: an essential tool for successful drug development. Drug Discov Today. 2005;10(21):1421–1433.CrossRefGoogle ScholarPubMed
Guth, BD, Germeyer, S, Kolb, W, et al. Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization. J Pharmacol Toxicol Methods. 2004;49(3):159–169.CrossRefGoogle ScholarPubMed
Stummann, TC, Bremer, S. The possible impact of human embryonic stem cells on safety pharmacological and toxicological assessments in drug discovery and drug development. Curr Stem Cell Res Ther. 2008;3(2):118–311.CrossRefGoogle ScholarPubMed

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