Abstract
Background and Objectives: The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine.
Methods: Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching.
Results: There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5 ms or less: 3.8 ms (90% CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90% CI 2.0, 8.0 ms) for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebo-corrected changes in MCS and QTcF values.
Conclusion: This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.
Similar content being viewed by others
References
Corcóstegui R, Labeaga L, Innerárity A, et al. Preclinical pharmacology of bilastine, a new selective histamine H1 receptor antagonist: receptor selectivity and in vitro antihistaminic activity. Drugs R D 2005; 6(6): 371–84
García-Gea C, Martínez-Colomer J, Antonijoan RM, et al. Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments. J Clin Psychopharmacol 2008; 28(6): 675–85
Horak F, Zieglmayer P, Zieglmayer R, et al. The effects of bilastine compared to cetirizine, fexofenadine, and placebo on allergen-induced nasal and occular symptoms in patients exposed to aeroallergen in the Vienne Challenge Chamber. Inflamm Res 2010; 59(5): 391–8
Kuna P, Bachert C, Nowacki Z, et al. Efficacy and safety of bilastine 20mg compared with cetirizine 10mg and placebo for the symptomatic treatment of seasonal allergic rhinitis: a randomized, double-blind, parallel-group study. Clin Exp Allergy 2009; 39(9): 1338–47
Bachert C, Kuna P, Sanquer F, et al. Comparison of the effacacy and safety of bilastine 20 mg vs desloratadine 5 mg in seasonal allergic rhinitis patients. Allergy 2009; 64(1): 158–65
Zuberbier T, Oanta A, Bogacka E, et al. Comparison of the effacacy and safety of bilastine 20mg vs levocetirizine 5mg for the treatment of chronic idiopathic urticaria: a multicentre, double-blind, randomized, placebo-controlled study. Allergy 2010; 65(4): 516–28
Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy 2010; 65Suppl. 93: 1–13
Tyl B, Kabbaj M, Azzam S, et al. Lack of significant effect of bilastine administered alone and with ketoconazole on ventricular repolarisation: results of a thorough QT study (TQTS) with QT-concentration analysis. J Clin Pharmacol 2011. Epub ahead of print
Food and Drug Administration (FDA). Guidance for Industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. October 2005 [online]. Available from URL: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129357.pdf [Accessed 2012 Feb 1]
Haverkamp W, Breithart G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Eur Heart J 2000; 21(15); 1216–31
Hoffmann P, Warner B. Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends. J Pharmacol Toxicol Methods 2006; 53(2): 87–105
Faes Farma S.A. Bilastine Summary. Data on file [online]. Available from URL: http://www.faes.es [Accessed 2011 Jan 10]
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350(10): 1013–22
Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996; 131(3): 472–80
Yoshida H, Sugiyama A, Satoh Y, et al. Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model. Circ J 2002; 66(8): 758–62
Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12(4): 411–20
Desai M, Li L, Desta Z, et al. Variability of heart rate correction methods for the QT interval. Br J Clin Pharmacol 2003; 55(6): 511–7
Hutmacher MM, Chapel S, Agin MA, et al. Performance characteristics for some typical QT study designs under the ICH E-14 guidance. J Clin Pharmacol 2008; 48(2): 215–24
Struijk JJ, Kanters JK, Andersen MP, et al. Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology. Med Biol Eng Comput 2006; 44(7): 543–9
Couderc JP, McNitt S, Xia J, et al. Repolarization morphology in adult LQT2 carriers with borderline prolonged QTc interval. Heart Rhythm 2006; 3(12): 1460–6
Kanters JK, Graff C, Andersen MP, et al. Long QT syndrome genotyping by electrocardiography: fact, fiction, or something in between? J Electrocardiol 2006; 39Suppl. 4: S1 19–22
Couderc JP, McNitt S, Hyrien O, et al. Improving the detection of subtle IKr-inhibition: assessing electrocardiographic abnormalities of repolarization induced by moxifloxacin. Drug Saf 2008; 31(3): 249–60
Couderc JP, Kaab S, Hinterseer M, et al. Baseline values and sotalol-induced changes of ventricular repolarization duration, heterogeneity, and instability in patients with a history of drug-induced torsades de pointes. J Clin Pharmacol 2009; 49(1): 6–16
Couderc JP, Vaglio M, Xia X, et al. Impaired T-amplitude adaptation to heart rate characterizes IKr inhibition in the congenital and acquired forms of the long QT syndrome. J Cardiovasc Electrophysiol 2007; 18(12): 1299–305
Porthan K, Viitasalo M, Jula A, et al. Predictive value of electrocardiographic QT interval and T-wave morphology parameters for all-cause and cardiovascular mortality in a general population. Heart Rhythm 2009; 6(8): 1202–8
Graff C, Andersen MP, Xue JQ, et al. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology. Drug Saf 2009; 32(7): 599–611
Nielsen J, Graff C, Hardahl T, et al. Sertindole causes distinct electrocardiographic T-wave morphology changes. Eur Neuropsychopharmacol 2009; 19(10): 702–7
Graff C, Matz J, Christensen EB, et al. Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138. J Clin Pharmacol 2009; 49(11): 1331–42
Graff C, Struijk JJ, Matz J, et al. Covariate analysis of QTc and T-wave morphology: new possibilities in the evaluation of drugs that affect cardiac repolarization. Clin Pharmacol Ther 2010; 88(1): 88–94
Andersen MP, Xue JQ, Graff C, et al. New descriptors of T-wave morphology are independent of heart rate. J Electrocardiol 2008; 41(6): 557–61
Pratt CM, Hertz RP, Ellis BE, et al. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1994; 73(5): 346–52
Xue JQ. Robust QT interval estimation: from algorithm to validation. Ann Noninvasive Electrocardiol 2009; 14Suppl. 1: S35–41
Lupoglazoff JM, Denjoy I, Berthet M, et al. Notched T waves on Holter recordings enhance detection of patients with LQT2 (HERG) mutations. Circulation 2001; 103(8): 1095–101
Dumaine R, Roy ML, Brown AM. Blockade of HERG and Kv1.5 by ketoconazole. J Pharmacol Exp Ther 1998; 286(2): 727–35
Chaikin P, Gillen MS, Malik M, et al. Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects. Br J Clin Pharmacol 2005; 59(3): 346–54
Berger RD, Kasper EK, Baughman KL, et al. Beat-to-beat QT interval variability: novel evidence for repoalrization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 1997; 96(5): 1557–65
Bilchick K, Viitasalo M, Oikarinen L, et al. Temporal repolarization lability differences among genotyped patients with the long QT syndrome. Am J Cardiol 2004; 94(10): 1312–6
Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30(2): 487–95
Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol 1997; 80(8A): 82G–9G
Kronstein P. Briefing book, April 7, 2009 PDAC serdolect (sertindole) tablets [online]. Available from URL: http://www.fda.gov [Accessed 2011 Jan 10]
Acknowledgements
No sources of funding were used in the preparation of this manuscript. CG, JJS, JKK, MPA and ET are authors of two patents describing the T-wave morphology method. BT has no disclosures. The authors thank Nathalie Blanco for providing data for the bilastine study and FAES.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Graff, C., Struijk, J.J., Kanters, J.K. et al. Effects of Bilastine on T-wave Morphology and the QTc Interval. Clin Drug Investig 32, 339–351 (2012). https://doi.org/10.2165/11599270-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11599270-000000000-00000